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GAMESS as a Free Quantum-Mechanical Platform for Drug Research.

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Current Topics in Medicinal Chemistry, 2012, 12, 000-000 1

GAMESS As a Free Quantum-Mechanical Platform for Drug Research

Yuri Alexeev1, Michael P. Mazanetz2, Osamu Ichihara2 and Dmitri G. Fedorov3,*

1
Argonne Leadership Computing Facility, Argonne National Laboratory, 9700 South Cass Avenue, Building 240, Ar-
gonne, IL 60439, USA; 2Evotec (UK) limited, 114 Milton Park, Abingdon, Oxfordshire, OX14 4SA, UK; 3NRI, National
Institute of Advanced Industrial Science and Technology, Central 2, Umezono 1-1-1, Tsukuba 305-8568, Japan

Abstract: Driven by a steady improvement of computational hardware and significant progress in ab initio method devel-
opment, quantum-mechanical approaches can now be applied to large biochemical systems and drug design. We review
the methods implemented in GAMESS, which are suitable to calculate large biochemical systems. An emphasis is put on
the fragment molecular orbital method (FMO) and quantum mechanics interfaced with molecular mechanics (QM/MM).
The use of FMO in the protein-ligand binding, structure-activity relationship (SAR) studies, fragment- and structure-based
drug design (FBDD/SBDD) is discussed in detail.
Keywords: Quantum chemistry, fragment molecular orbital, drug design, ab initio, GAMESS, FMO, QM/MM, FBDD, SBDD.

1. INTRODUCTION try, is quickly disappearing. We also note that overall QM

Molecular mechanics (MM) has been very successfully
applied to many systems in biochemistry [1]. Many elaborate
force fields such as CHARMM [2] or AMBER [3, 4] have
been developed and highly tuned to the studies of biochemi-
cal systems. The traditional force fields offer high computa-
tional efficiency, however, the parameterization and the sim-
plistic models have very considerable limitations. Two main
drawbacks of the traditional force fields, the neglect of the
polarization and charge transfer (CT), have been the subject
of developing a new generation of force fields [5-10]. Fre-
quently, parameters for force fields are generated from quan-
tum-mechanical (QM) calculations of model systems. The
question arises to the transferability of those parameters,
which in the language of physics can be formulated as the
importance of many-body effects in describing physical in-
teractions. Importantly, the studies of chemical reactions
with bond breaking are typically conducted with QM ap-
proaches.
The reason why relatively few biochemical scientists
have taken advantage of QM approaches lies in several fac-
tors. One is their large computation cost. However, driven by
both the remarkable progress in QM method development
and the amazing pace in computational hardware improve-
ment, with the revolutionary advent of multicore CPUs (a
single node with 48 cores is readily available) and GPUs
(with hundreds of computing units), one can now routinely
perform calculations of systems containing hundreds and
thousands of atoms. The other factor is the difficulty in set-
ting up and running the calculations. Many excellent graphi-
cal packages enable users to employ QM methods with rela-
tive ease. The aura of being too slow and difficult for the
non-initiated, which has long loomed over quantum chemis-
*Address correspondence to this author at NRI, National Institute of Ad-
vanced Industrial Science and Technology, Central 2, Umezono 1-1-1,
Tsukuba 305-8568, Japan; Tel: +81-29-861-7218; Fax: +81-29-851-5426;
E-mail: d.g.fedorov@aist.go.jp
calculations are more standard and transparent than for ex-
ample, force fields.
The other factor of time scale, that is, the need to take
into account the entropy and consider dynamic aspects of
biochemical process on a realistic time scale, still remains a
major problem. It should be said here that while for force
fields one can get away with the dubious idea of simulating
processes at an unphysically high temperature to accelerate
them, the same will not work with QM, because bonds are
not fixed by springs and will easily break as temperature
increases.
The use of QM in drug research [11] is one of the most
exciting developments in the recent years which has the po-
tential to revolutionize this field. QM methods have impor-
tant advantages over MM approaches. Firstly, QM has no
implicit parameterization and relies only on the use of well-
known physical constants such as the velocity of light and
the masses and charges of atoms. The molecular properties
and geometries are obtained by solving the differential
Schrödinger equation [12-14]. Unfortunately, the equation
can be solved directly only for only very small systems [15,
16].
A number of QM methods based on various models and
assumptions on the structure of the wave function have been
developed. Density functional theory (DFT) [17] owes its
popularity to relatively low cost and a fairly good accuracy,
and systems of biochemical size are becoming accessible
[18]. Recently developed DFT methods deliver bond lengths
for organic molecules within 0.02 Å and an absolute energy
error within 3 kcal/mol [14] in comparison to experiment.
However, such high accuracy comes at a hefty computer
time price. Until recently, only fairly small systems (~100
atoms) could be computed because the cost of calculations
scales at least cubically with respect to the system size.
A number of ab initio [19, 20] and fragment-based [21,
22] linearly scaling methods have been proposed, which

1568-0266/12 $58.00+.00 © 2012 Bentham Science Publishers

2 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18
compete with semi-empirical approaches [23, 24]. QM
methods are indispensable for describing chemical reactions
and excited states, as well as for free radicals [25].
The fragment molecular orbital (FMO) method [26] is
one of the fragment-based methods. Impressive results can
be achieved when both linear scaling QM approaches and
supercomputing technologies are combined [27]. For exam-
ple, FMO energy calculation of the receptor-ligand system
with size of 17,767 atoms takes only ~54 minutes on Blue
Gene/P 40,960 CPU cores at the RHF level of theory and 6-
31G* basis set [28]. With the current pace of advances in
both computer technology and algorithms, a wide use of QM
simulations for realistic biochemical systems is expected in
the near future.
Ligand binding is a very complex phenomenon and both
enthalpic and entropic contributions need to be appropriately
dealt with in order to estimate the free energy of binding
accurately. It is important to mention that QM methods de-
scribed in this paper are used exclusively for computing en-
thalpy and solvation energy. Computation of configurational
entropy is obviously important to obtain complete energetic
picture of ligand binding but it is notoriously difficult and it
is often not practical to use quantum-chemical methods for
this purpose. Classical molecular dynamics simulations (for
example: quasiharmonic analysis with the covariance) [29]
are commonly used to estimate configurational entropy
which will not be covered in this paper. However, in medici-
nal chemistry program, particularly in lead optimization
stage, ligands of interest share a common molecular frame-
work and it is often safe to assume that they the entropic
contributions cancel out. We would also like to emphasize
that binding free energy is not the only property useful for
drug design. QM methods, particularly together with energy
decomposition analyses, can also provide much richer in-
formation on the nature of protein-ligand interactions to me-
dicinal chemists for ligand design. For example, non-
classical interactions such as CH-
and halogen-
etc can be
readily identified, which are otherwise hard to detect and
quantify.
In this review we focus on in silico drug design methods
and applications of QM methods implemented in the quan-
tum chemistry package called General Atomic and Molecu-
lar Structure System (GAMESS) [30, 31]. There are several
excellent general reviews of GAMESS by its principal de-
velopers, Gordon and Schmidt [32, 33], whereas we only
describe applications of GAMESS relevant to drug research.
We cover in detail the following studies: pKa estimation,
geometry optimization, computation of ligand binding en-
ergy, definition of quantitative structure-activity relationship
(QSAR) descriptors, and analysis of the ligand-receptor in-
teraction energies with the goal of designing new drugs with
a better affinity and specificity. We conclude with an outlook
on a future use of QM in drug research, with the hope to
provide convincing arguments of the great potential held by
QM methods.
2. QUANTUM-MECHANICAL METHODS
GAMESS OVERVIEW
The history of GAMESS is described in detail by Gordon
and Schmidt [33]. At some point, GAMESS-UK [34] and PC
Alexeev et al.
GAMESS (now renamed Firefly) [35] branched off from the
main project GAMESS-US [36]. The three branches share
much of the source code, and the input and output file struc-
ture, but a lot of independent new development has been
invested in each project so that they have a substantially dif-
ferent functionality and performance. GAMESSPlus is an
add-on with additional functionality for GAMESS-US, in-
cluding solvation models, DFT functionals and QM/MM
capability [37].
While Firefly is designed specifically for Intel-
compatible CPUs, GAMESS-US and GAMESS-UK also run
on other types of architecture: in particular, when a UNIX
operating system is available. Source code can be obtained
for the former two projects, and precompiled binaries are
provided for all three. GAMESS-UK is available for free for
academic users in the UK, while GAMESS-US and Firefly
are free for both industry and academics. WinGAMESS is a
GAMESS-US binary precompiled for Microsoft Windows.
The GAMESS forum [38] can be used for discussions.
GAMESS can take advantage of massively parallel com-
puters. For GAMESS-US, distributed data interface (DDI)
[39] was developed which is one sided-communication mes-
sage passing library that works on top of either Unix sockets
or standard MPI [40]. DDI was used to parallelize various ab
initio QM methods [41-43]. Generalized DDI (GDDI) [44]
based on an efficient node grouping can be utilized with
some methods such as FMO on large supercomputers. For
parallelization, Firefly uses MPI in combination with the
thread-based Point-to-Point (P2P) message oriented inter-
face; the latter works via Ethernet (using TCP/IP sockets),
shared memory or InfiniBand. GAMESS-UK can be paral-
lelized with the Global Array toolkit or MPI.
Here we list the QM methods which are of particular
relevance to drug research. The most basic QM method is
Hartree-Fock (HF), which exists in the restricted (RHF) and
unrestricted (UHF) varieties. The former is used for closed
shell systems such as organic molecules and proteins, while
the latter finds it use mainly for systems with transition met-
als or radicals. Two main branches of methods improving on
HF have evolved in QM. One is DFT, which offers a similar
computational cost to RHF, and is in general very successful
in many systems without nearly degenerate orbital spaces.
The other is given by the explicit treatment of the electron
correlation, for which there is a well arranged ladder of
methods offering a clear way to improve the accuracy.
Among these, second order Møller–Plesset perturbation the-
ory (MP2) is most readily useful for large systems, although
more advanced methods can be also applied in some cases,
such as coupled cluster (CC) theory.
For DFT, there are many functionals whose choice is
driven by experience. B3LYP [45] and PBE [46] are popu-
lar, and among recent development we mention long-range
corrected CAM-B3LYP [47], and M06 [48]. The latter per-
forms especially well for organometallic and inorganometal-
lic chemistry and for non-covalent interactions. An ad hoc
AND way of improving DFT is to include an empirically param-
eterized dispersion correction [49], which can also be used
for RHF. For MP2, there is some choice of methods: the
spin-component scaled version of MP2 (SCS-MP2) [50], and
GAMESS for Drug Research
accelerated regular MP2, based on the resolution of the iden-
tity (RI-MP2) [51].
We focus on the methods which are particularly suitable
to calculations of large systems: the fragment molecular or-
bital (FMO) method and QM/MM, performed by interfacing
GAMESS with MM programs CHARMM (Chemistry at
HARvard Macromolecular Mechanics) [52] or TINKER
[53].
3. METHODS FOR LARGE SYSTEMS
The choice of an optimal method depends on the type of
calculations and should pursue the balance between the accu-
racy and speed. The latter is an especially relevant factor for
drug research because of the need for providing useful in-
formation for ligand design to chemists during rapidly mov-
ing medicinal chemistry projects. A large ligand-receptor
system can be split into three major regions: an active site
with a ligand, the rest of the protein, and solvent. Ideally,
one would prefer to treat the whole system by QM, but to
achieve high speed and accuracy each region can be treated
with different models. QM/MM methods important for drug
research are reviewed in detail below.
QM/MM is suitable for fast high-throughput calculations,
but for an analysis of an active site revealing ligand-receptor
interaction details, full QM methods like FMO are powerful
alternatives. The reason why it is desirable to perform QM
calculations of the whole system can be a large ligand having
multiple weak van der Waals interactions with the receptor,
multiple successive chemical reactions in the active site, or
an excited state involving delocalized CT.
3.1. Full ab initio
In addition to a high computational cost of traditional ab
initio methods, the memory requirements are also high, es-
pecially for MP2 and CC. Even in the most economic RHF
and DFT, the memory requirement scales quadratically with
the system size, which eventually becomes a problem. Usu-
ally, there are several matrices one has to store. Assuming
for simplicity that one stores the Fock, density, overlap and
MO matrices, this gives 4
8
N2 bytes, where N is the num-
ber of basis functions. For N=10000 (approximately 1000
atoms with 6-31G*), this is 3.2 GB. Unless the matrices are
distributed among computer nodes, this amount of memory
is required per CPU core, plus some memory is taken by OS
and the program itself. Even for a modern workstation 4 GB
per CPU core is a significant amount, and large supercom-
puters such as Blue Gene typically have very moderate
amount of memory per core.
Thus, Alexeev et al. [42] developed a self-consistent
field (SCF) algorithm for RHF in GAMESS-US, in which
large matrices are distributed between nodes. On the other
hand, to overcome steep computational cost of QM, one can
use the fast multipole method (FMM) [54] to accelerate two-
electron integrals in large systems, which was implemented
[55] in GAMESS-US. Ishimura et al. developed an efficient
OpenMP/MPI parallelization [56] capable of using many
nodes in ab initio calculations. Despite this method devel-
opment, systems of biological size are still hard to treat with
fully ab initio methods. Among very few published applica-
Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 3
tions of GAMESS, one can find the study of HIV-1 by
Weltman et al. [57].
3.2. Fragment-Based Approaches
The following low-scaling ab initio based methods are
available in GAMESS-US: effective fragment potential
(EFP) [8], elongation method (ELG) [58], divide-and-
conquer (DC) approach [59] and FMO [26]. The former is a
QM-parameterized force field and we describe it below to-
gether with other force fields. The ELG method is primarily
used for polymers, although some preliminary probing has
been performed on DNA [60, 61] and the applicability to
biochemical systems has been discussed [62]. DC methods
in GAMESS-US have so far not been applied to biochemical
systems, so we do not describe them any further.
The FMO method [26] has been widely applied to large
molecular systems, including a recent geometry optimization
of a 0.1 μm BN nanoring [63]. There are several reviews of
FMO [22, 64, 65], book chapters [66-68] and a full book on
FMO [69], which can be used for a more detailed and con-
cise study of FMO. Here we provide an overall picture with-
out giving too many technical details. The relation of FMO
to other methods has been recently discussed [22, 65] and we
do not address it here.
The idea of functional groups is paramount to chemistry.
This is because the functional groups, if properly defined,
retain to a large extent their physical properties in various
molecular systems, under the perturbing influence of envi-
ronment (e.g., other functional groups). This is exactly the
basic principle behind fragment-based methods such as
FMO. By taking advantage of chemical knowledge, one can
define groups of atoms, called fragments, which are de-
scribed by QM, and an interaction between them. Clearly,
the success of such an approach relies on the efficiency of
treating the interactions.
In FMO, the electrostatic interaction is accounted for by
including the polarizing electrostatic field in all fragment
calculations. The field corresponds to the whole system, and
it is computed using the electron densities and nuclei of all
fragments (called monomers). The other key step is to calcu-
late pairs of fragments (dimers) using QM, in order to de-
scribe non-electrostatic interactions, such as exchange-
repulsion and CT. Alternatively, there is also effective FMO
(EFMO) [70], which differs from regular FMO in the de-
scription of the electrostatics. EFMO can be used in many
ways similar to FMO, for example, to do QM calculations of
proteins [71].
Treatment of covalent bond detachment during fragmen-
tation is a technical issue well described elsewhere [65, 69].
Here we only mention that the electron density distribution
of a detached bond is assigned to a single fragment, i.e.,
bonds are detached heterolytically and without the addition
of hydrogen caps. The detached bonds are saturated by the
embedding potential. The methodology ensures that for
closed shell systems the fragments are also closed shell, and
neutral unless some charged functional group is present.
For practical applications, an important question is, how
to define fragments? There is a rather simple answer for
FMO, and the main principle is to minimize the CT between
4 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18
fragments. This is because CT is accounted for in FMO with
dimer calculation, i.e., it is limited to two-body contributions
only. Charge transfers between pairs of fragments are cou-
pled, i.e., there are many-body CT effects. The same applies
to exchange-repulsion (a quantum effect originating from the
Pauli exclusion principle) and the dispersion. All of these
effects are typically localized so that one can meaningfully
define fragments. When CT is not localized, then one cannot
fragment the system, e.g., conjugated systems such as aro-
matic ring systems or donor-acceptor metal complexes. For
the latter type, assigning a metal cation as a separate frag-
ment will result in every substantial CT between the metal
and ligands, thus leading to a poor accuracy. Salt bridges
between positively and negatively charged amino acid resi-
dues are also prone to a large CT, and one can combine them
into a single fragment for a better accuracy.
Biochemical systems are composed of a few dozens of
standard units, enabling an easy automatic fragmentation.
The caveat here is that for polypeptides, there is a consider-
able CT across a peptide bond, so that one cannot fragment
it. Instead, polypeptides are fragmented at C
, and residues
in FMO become residue fragments shifted by one carboxyl
group relative to the conventional residues. To distinguish
between the conventional residues and residue fragments, we
often insert a dash in the latter, e.g., Trp-6. Polysaccharides
are fragmented into sugar units, and nucleic acids such as
DNA or RNA into bases. Such automatic fragmentation can
be readily performed using Facio [72].
Ligands leave some freedom to the user. There are two
reasons to divide a large ligand into several fragments. If a
ligand is large, it takes relatively long to compute, especially
for correlated methods such as MP2. Also, ligands often
have some subunits and it desirable to analyze the properties
of these subunits such as the interaction energy between a
piece of the ligand and a residue fragment in a protein. This
naturally shows the connection between FMO and fragment-
based drug design (FBDD). The small molecules (<300
dalton) used in FBDD can be treated as FMO fragments dur-
ing hit optimization and, potentially, structure-based drug
design (SBDD). When fragmenting ligands, one should be
careful about CT, and ligands are often difficult to divide
because they can be composed of extended aromatic systems
with delocalized electrons. Technically, the division of
ligands is usually a manual process (unless ligands are poly-
peptides or other standard systems). Programs such as Facio
[72] greatly facilitate it requiring only clicking on the bonds
which should be detached in forming fragments.
When in doubt, one can always do a back check. Because
this is useful, especially for experiments with novel systems,
we describe it briefly. After an FMO calculation is per-
formed, one gets the properties such as the CT between
fragments. By looking at the values of CT, one can form a
fairly good idea if the fragmentation was successful. Typical
CT amounts for a hydrogen bond are 0.02-0.05 electrons or
so. Any CT on this order should be taken as appropriate in
general. Larger values should be given some thought, espe-
cially if they exceed 0.1 electron.
Next, we give the basic FMO equation and briefly de-
scribe how an FMO calculation proceeds.
Alexeev et al.
(1)
First, the electronic state of each fragment is calculated
self-consistently with the polarizing embedding potential
describing the rest of the system. This gives the energy of
fragments EI. Next, the electronic state of fragment pairs is
computed once in the embedding potential, producing EIJ.
These energies are assembled in Eq. 1 above, giving the total
energy of the system E. By taking an analytic derivative [73,
74], one can easily obtain the gradient, which can be used for
geometry optimizations [75-77]. We note that the total gra-
dient E is with respect to the atoms in the whole system,
and once the vector is constructed, it can be used in any
standard optimizer. Alternatively, one can define a frozen
domain (FD) in the FMO/FD method see Fig. (1D) [77] tak-
ing advantage of the fragmentation, as described in more
detail below.
The computational cost of FMO is determined by the
number of fragments N, and the number of dimers N2. By
taking advantage of the spatial separation [78] between
fragments, all dimers are divided into two groups. For the
first group with a short separation, one has to perform QM
calculations. The number of such dimers scales nearly line-
arly with the system size, because for each fragment there is
a small number of other close fragments, and this number is
independent of N. The number of remotely separated dimers
scales quadratically, however, their calculation does not re-
quire QM calculations because the interaction is essentially
electrostatic in nature. Thus the overall scaling of FMO is
usually nearly linear, and there is an ongoing work to im-
prove it [79, 80].
Many common methods have been made available for
use in FMO, such as MP2 [81] or DFT [82]. Free radicals
can be described with both restricted [83, 84] and unre-
stricted [85] open shell methods. For instance, transition
metal containing enzymes or complexes can be created with
the unrestricted FMO method. For a detailed description of
available methods, refer to the recent review [65]. As pointed
out above, FMO does not give the same total energy as a
regular ab initio QM calculation. This is because of some
many-body effects neglected in FMO. The above equation
corresponds to the two-body FMO (FMO2); higher-order
FMO3 [86] and FMO4 [87] greatly improve the accuracy at
the additional computational cost of computing trimers and
tetramers, respectively. The accuracy of FMO depends on
the appropriateness of fragmentation and also on the basis
set (large basis sets especially with diffuse functions have
lower accuracy, caused by large many-body effects). A bet-
ter accuracy can be obtained with larger fragments, for ex-
ample, a division into two residues per fragment is often
used for accurate energetics. In many systems containing
several hundreds of atoms the error of the FMO total energy
E was shown to be on the order of several kcal/mol com-
pared to full ab initio, but it can be worse if there is a large
CT. The accuracy of the relative energies, e.g. a protein-
ligand interaction energy, should be expected to be much
better than the accuracy of the absolute energies.
There are two major advantages of fragmentation. Firstly,
fragmentation has high computation efficiency, because only
GAMESS for Drug Research
small subsystems (fragments and their pairs) are computed,
which can also be efficiently parallelized. Inexpensive PC
clusters consisting of several nodes connected by Gigabit
Ethernet can nowadays have a hundred CPU cores or more,
providing a powerful tool for applications of FMO to drug
design. On the high end, FMO can be used on supercomput-
ers [27] taking advantage of many thousands of CPU cores.
The second advantage is the fragment properties computed
along with the total energy E in the FMO method. Some of
these properties are automatically generated in any calcula-
tion, and some are optional requiring additional computa-
tions. The fragment properties in FMO are: multipole mo-
ments of fragments (dipole, quadrupole etc), fragment po-
larization energies and molecular orbitals of fragments. The
properties of fragment pairs are the pair interaction energies
and the CT between them. In solution, there are also the cor-
responding solute-solvent properties. The total properties
include the energy, its gradient, atomic charges and molecu-
lar orbitals.
Now we describe the pair interaction energies at some
length. As can be inferred from eq. 1, the difference EIJ-EI-EJ
is the pair interaction energy between fragments I and J. It
also includes the embedding potential (because each of the
fragment or dimer energies is computed with it), and thus
contains explicit many-body effects, complicating the analy-
sis. Therefore, one usually uses a different form of the pair
interaction energy based on the internal energies of frag-
ments and their dimers (i.e., with the embedding potential
separated). In this case one obtains the total values, which
can be decomposed further into components using the pair
interaction energy (PIE) decomposition analysis (PIEDA)
routines implemented in FMO [88-91].
(2)
The components of the total values (INT) are: the elec-
trostatics (ES), exchange-repulsion (EX), CT and higher
order terms (CT+mix), dispersion (DI) and solvent screening
(SOLV). The latter component [91] is defined for the po-
larizable continuum model (PCM). The polarization is an
electrostatic effect, and it can also be computed in PIEDA
with the definition of a reference non-interacting state, and
monomer energies EI, which are affected by the polarization.
As described below, pair interaction energies between ligand
and protein residues provide useful descriptors in QSAR.
3.3. Molecular Mechanics
Standard force fields, such as Amber [3, 4], CHARMM
[52], OPLS [92], and MMFF [93], can be used in GAMESS
via an interface to CHARMM or Tinker. In addition to that,
there is also a more advanced ab initio derived force field,
EFP. There are many excellent reviews of EFP elsewhere
[22, 94], and here we only briefly mention its main points.
EFP is a rigid model, i.e., its internal geometry always re-
mains frozen, although fragments can move relative to each
other. The original EFP (now called EFP1) was parameter-
ized for water by fitting its terms to ab initio calculations of
water dimer as a function of distance [8]. EFP1 was success-
fully applied to a wide array of problems [95, 96] modeling
solvent effects on chemical reactions in ground and elec-
tronically excited states.
Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 5
A general potential EFP2 [94] was developed with an
automatic generation of its parameters, which is in principle
applicable to any system. Both EFP1 and EFP2 include the
effects of the polarization and CT, and EFP2 also has an ex-
plicit dispersion [97]. EFP2 is fully developed for EFP-EFP
interactions, and a QM-EFP2 interface is also available. The
performance of EFP2 has been demonstrated on a variety of
molecular systems [98, 99]. EFP1 was also applied to pro-
teins [100], using frozen localized orbitals on fragment
boundaries. EFP1 was interfaced with FMO [101] and can be
used to describe explicit solvent in FMO.
3.4. QM/MM Methods
There are few conceptual choices to accurately compute
chemical reactions in the active site of a protein. One is to
apply ab initio QM methods which would limit the size be-
cause of the computational time and memory limitations. A
more attractive option is a compromise: the active site is
treated accurately with QM while the rest of the system is
treated with MM. The QM region is usually chosen to be
large enough [102] to include all important electronic struc-
ture effects. The MM region introduces structural constraints
and environmental effects (electrostatic and van der Waals
interactions) acting upon the QM region. There are some
disadvantages of QM/MM: a number of successive chemical
reactions in an active site may force a very large QM region
or a multiple redefinition of a smaller one. Also, artifacts in
the QM/MM interface may lower the accuracy of this ap-
proach. In addition, there is the complexity of setting up cal-
culations. The coupling between the QM and MM regions is
the central issue of any QM/MM method defining its accu-
racy and general usefulness.
There are a large number of implementations of
QM/MM, but we cover only those relevant to GAMESS in
chronological order. Detailed QM/MM reviews can be found
elsewhere [103-105]. Firstly we mention the implementation
by Field et al. [106] of the QM/MM interface between
CHARMM and QUANTUM codes, which was later ex-
tended to CHARMM/GAMESS interface by Lee et al. [107].
The partitioned system is described by the effective Hamil-
tonian:
(3)
where and are the Hamiltonians of the QM and
MM regions, respectively. represents the electrostatic
and van der Waals interactions between the QM and MM
atoms, whereas describes periodic or stochastic
boundary effects in the system. The overall setup is shown
on Fig. (1A). To treat a covalent bond between QM and MM
atoms, link atoms are utilized, which are treated as regular
QM atoms interacting with the atom charges in the MM re-
gion. In CHARMM, link atoms have no charge, no van der
Waals parameters and they do not appear in the MM energy
terms. The described approach was extensively tested on
small systems and it was found that depending on the parti-
tioning to QM and MM regions one can well reproduce full
QM geometries [108]. Although this is a well-tested method
to treat QM/MM interface, the alternative frozen orbital
6 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18
method [109] is considered more accurate [103]. Cui and
Karplus [110] developed analytical second energy deriva-
tives for QM/MM, which enables an evaluation of vibra-
tional frequencies and infrared intensities in large systems.
Fig. (1). Different composite methods. (A) QM/MM in GAMESS/
CHARMM. (B) QM/MM/PCM in GAMESS/CHARMM. (C)
QM/EFP/PCM in GAMESS. (D) FMO/FD implemented in
GAMESS, where AD and FD are active and frozen domains, re-
spectively.
For an efficient geometry optimization Maseras and
Morokuma proposed a variation of QM/MM called the inte-
grated molecular orbital molecular mechanics (IMOMM)
[111] which was later implemented in GAMESS-US via an
interface with Tinker by Shoemaker et al. [112] in their sur-
face IMOMM (SIMOMM) method. IMOMM differs from
QM/MM in neglecting the electronic embedding (there is no
polarization of the QM region by MM).
EFP is interfaced with most of QM methods imple-
mented in GAMESS-US. As in all QM/MM methods cova-
lent bond division represents a challenge, which in EFP was
addressed by utilizing frozen localized molecular orbitals
(LMOs) [100]. In QM/EFP one introduces the buffer region
with LMOs frozen during SCF, see Fig. (1C). Computations
of the proton affinity with QM/EFP for a number of small
organic systems demonstrated that this method consistently
reproduced full ab initio values within 0.4 kcal/mol [100].
Nemukhin and coworkers proposed to use flexible fragments
in QM/EFP to treat biochemical systems [113, 114]. Alterna-
tively to QM/EFP, one can do QM/MM calculations in
GAMESS with polarizable force fields using QuanPol [115].
There are few QM/MM platforms which support multiple
QM and MM packages. In particular, ChemShell developed
by Sherwood et al. [116] currently supports many QM pro-
grams including GAMESS-UK. Another platform is the
Alexeev et al.
QMMM program developed by Truhlar and coworkers
[117], which supports GAMESS-US.
3.5. Solvation Models
Solvation effects can play a crucial role in the structural
and dynamical properties of a ligand interacting with the
receptor. The solvation effects, broadly divided into non-
polar and electrostatic contributions, can be described by
explicit or implicit solvation models or their combination
called the supermolecule approach [118, 119]. In QM meth-
ods, the implicit solvation models usually rely on solving the
Poisson equation [120] numerically. The implicit solvation
models implemented in GAMESS-US are the Onsager cavity
model or self-consistent reaction field (SCRF) [121], con-
ductor-like screening model (COSMO) [122], PCM [120],
surface and simulation of volume polarization for electrostat-
ics (SS(V)PE) [123], and solvation model 6 with temperature
dependence (SM6T) [124]. GAMESS-UK supports SCRF,
PCM, and direct reaction field (DRF) [125]. In Firefly, one
can use SCRF or PCM. On the other hand, explicit water
molecules can be included in the QM region, or treated by
MM (EFP).
The implicit solvation models are computationally
cheaper compared to explicit description of water, but they
sometimes have poor accuracy, especially if water molecules
in the first solvation shell form strong hydrogen bonds with
the solute. Water molecules often coordinate a ligand and are
vital for a proper description of the structure and energetics.
In the supermolecule approach the first solvation shell is
described explicitly, however, a statistical sampling of water
configurations should be performed, for example, based on
molecular dynamics or Monte Carlo methods. Water mole-
cules can be treated with MM instead of QM, for example, in
QM/EFP.
A popular implicit model for interfacing with QM/MM
methods is PCM, where a cavity surrounding the solute is
formed by combining spheres centered on each atom of the
solute. The cavity surface is divided into many tesserae, and
each tessera has its own surface charge determined by the
electric field on it. The charges on the tesserae are solved
self-consistently with the electronic state of the solute. Con-
sequently, those charges make direct contributions to the
energy and the gradient of the solute. In PCM the free energy
includes the following solvent-related term :
(4)
where the electrostatic (es), repulsion (rep) and dispersion
(disp) solute-solvent interactions are added to the cavitation
(cav) energy. The PCM can be combined with most QM
methods. The main problem of PCM is the parameterization
of atomic radii which defines the cavity shape. There are a
number of sets of radii, such as van der Waals radii or
United Atom for Hartree-Fock (UAHF) [126]. Depending on
the choice of the radii, the results can significantly differ.
Cui et al. interfaced PCM with QM/MM implemented in
GAMESS/CHARMM [127], see Fig. (1B). It can be consid-
ered a variant of ONIOM-PCM [128]. One of the ways to
apply QM/MM/PCM is to treat the ligand with QM, and the
GAMESS for Drug Research
rest of the receptor and the water molecules in the first solva-
tion shell by MM (a supermolecule approach), and describe
continuum by PCM. QM/MM/PCM was applied to study
small model systems. In particular, the relative stability of
the neutral and zwitterionic forms of glycine in solution was
correctly reproduced [127].
Bandyopadhyay et al. interfaced EFP with PCM [129] in
a similar way as Cui interfaced PCM with QM/MM. Later,
Li et al. implemented a more computationally efficient and
parallelized version of the EFP/PCM solver [130]. In the
latter case, EFP-induced dipoles and PCM-induced charges
are iterated to self-consistency during convergence of the
electronic state. The analytical gradients were developed also
[119] enabling an efficient geometry optimization.
QM/EFP/PCM model shown in Fig. (1C) was successfully
applied to study stability of glycine in solution [129] and pKa
prediction [131].
PCM was interfaced with FMO by Fedorov et al. [132].
Later the analytical gradient was implemented [133]. In
FMO/PCM the solvent is treated as in other QM/PCM ap-
proaches: there is a solvent cavity surrounding the whole
solute, and in each fragment calculation one has to add the
electrostatic field of the point charges on the cavity. These
charges are induced by the electronic state of the solute, rep-
resented by the electrostatic potential. In FMO, it is com-
puted from monomer and dimer contributions. Several levels
of FMO/PCM were developed for the many-body expansion
of this potential. The cheapest level of PCM[1] is based on
only monomer contributions to the solute potential inducing
solvent charges. In PCM[1(2)], dimer corrections are also
added in the perturbative fashion to PCM[1]. The former
method is often used for an accurate evaluation of the ener-
getics while the latter is mainly used in geometry optimiza-
tions. Recently, an improved PCM
1 model for FMO was
developed by Nagata et al. [134], which is both accurate and
efficient, being a modification of PCM[1].
In PIEDA/PCM, the physical picture of the solvent
screening in PCM was elucidated [91]: the screening arises
because of the charges induced on the solvent, which com-
pensate the direct Coulomb interaction between charges in
the solute. In other words, those induced charges are directly
related to the dielectric constant. The local screening can
take values, very different from those determined by the bulk
macroscopic constant, thus the actual interaction picture in
the solute has many local features determined by its local
electrostatic field, and often unexpected results are seen be-
cause of the of the many-body electrostatic effects. Details of
these interactions can be readily studied with FMO/PCM,
based on fragments and their induced charges.
4. SOFTWARE TOOLS
There are a number of graphical programs to generate
input files and visualize GAMESS output. MacMolPlt [135]
was developed exclusively as a graphical user interface for
GAMESS-US. It allows preparing input files, displaying and
animating molecules, normal modes of vibrations, reaction
paths, as well as plotting electron densities and molecular
electrostatic potentials. Precompiled binaries can be down-
loaded for free [136]. FMOutil [137] offers a simple inter-
face to converting PDB files into GAMESS input for FMO
Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 7
calculations, automatic protonation and other capabilities. A
set of tools for FMO (FMOtools package) [138] is developed
by Alexeev specifically for FMO implemented in GAMESS-
US. The package has a Web interface and consists of four
modules (FMOcheck, FMOsolv, FMOgen and FMOres)
which allow checking PDB structure for consistency errors,
fragmenting proteins and ligands, visualizing fragments in-
teractively in Jmol, solvating the system, generating
GAMESS input files, running short GAMESS-US simula-
tion to test input file syntax, analyzing and visualizing
GAMESS-US output (including the pair interaction ener-
gies). FMOtools is the only package which supports input
generation and analysis for the FMO/FD method. FragIt is
developed for a smart fragmentation of large molecular sys-
tems based on chemical patterns [139, 140].
There are many graphical programs which support multi-
ple GAMESS packages and other QM programs. One of
such programs is Facio [72] which is freely distributed as a
precompiled binary. Facio supports GAMESS-US and Fire-
fly and can do molecular modeling, build input files, and
visualize results. It has a very advanced GAMESS/FMO
interface, which can automatically fragment polypeptides,
saccharides, nucleotides or any combination thereof, possi-
bly in the presence of other standalone molecules (ligand or
explicit solvent). It can also manually fragment ligands or
other systems, by clicking bonds to be detached. The results
of FMO calculations can be visualized, in the form of inter-
active maps and graphs of pair interactions, with a clear link
to the structure. In difficult cases, for instance, if metal
cations or metal-coordinated fragments are present, the user
may need to intervene and manually change the automatic
fragmentation to prevent excessive CT.
There are other universal graphical programs such as
Winmostar [141, 142], Avogadro [143], Molden [144],
ChemCraft [145], GDIS [146], MaSK [147], and Gabedit
[148], which offer some support of GAMESS programs.
CCP1 GUI [149] is an advanced graphical interface for
GAMESS-UK, specifically developed to support many of its
features. PC-GUI [150] and Ascalaph Quantum [151] are
graphical interfaces for Firefly. Furthermore, there is an
FMO interface extension to the drug discovery software
package MOE that is available from the SVL Exchange
[152]. This GUI allows for the preparation of FMO input
files for GAMESS and for the visualization of the output
from FMO, such as PIEDA.
Using web interfaces for visualizing molecules, generat-
ing input files, and analyzing results is an exciting new de-
velopment owing to the rapid development of web technol-
ogy in recent years. An appealing advantage for users is that
there is no need to install and update software. A number of
graphical viewers for 3D chemical structures were written in
Java which allows running program as a web browser applet
and standalone Java application on all modern operating sys-
tems. One of such programs is Jmol [153] which was used in
the FMOtools interface [138]. WebMO [154] also supports
GAMESS.
5. MODELING MOLECULAR SYSTEMS
The initial preparation of the geometry structure and pro-
tonation is the first crucial step in drug design. The accuracy
8 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18
of the predicted ligand binding affinity is directly related to
the quality of the geometric structure of the ligand-receptor
complex. The correct protonation of the ionizable amino
acids plays an important role in the prediction of protein sta-
bility, binding ability, and catalytic activity. Since the initial
preparation can affect the mechanism of a chemical reaction
or the binding of a ligand to the receptor, accurate methods
such as FMO and EFP can be helpful in a reliable initial
preparation.
5.1. pKa Prediction
The early approaches [155] to compute pKa in proteins
considered only the interactions between the charged groups
represented as point charges in dielectric continuum, and
solved the electrostatic Poisson-Boltzmann equation. These
approaches failed to take into account other important inter-
actions, notably the hydrogen bonds which affect pKa of
ionizable amino acids. Besides that, the description of the
interactions by point charges ignoring the electronic struc-
ture can produce a significant error. One solution is to treat
the short-range interactions with QM and the long-range
interactions with MM in the QM/MM approach. MM can use
a classical force field or the more sophisticated EFP. As a
way to improve the speed of calculations, EFP fragments far
from QM region can be replaced by force fields as shown in
Fig. (1C).
Such approach was used to predict the pKa value of
Lys55 in protein OMTKY3[156], where the following way
was used to compute pKa to eliminate the systematic error in
the free energy. For the reaction,
Lys55H++ CH3NH2
Lys55 + CH3NH3+ (5)
the following relation was used,
pKa (Lys55H+) = 10.6 + ([G(Lys55) - G(Lys55H+)] -
[G(CH3NH2) - G(CH3NH3+)])/1.36 (6)
where 10.6 is the experimentally determined pKa of methy-
lamine (instead of methylamine any chemical compound can
be used, which donates or accepts a proton with an accurate
experimentally known pKa). The free energy G of each com-
pound is a sum of the ground state electronic energy and the
solvation energy. Only Lys55 and Tyr20 side chains in OM-
TKY3 were treated by QM and the rest of the system was
treated with an EFP. The computed pKa for Lys55 was 11.4
which agrees well with experimentally determined pKa of
11.1 [157]. More details can be found elsewhere [158] in-
cluding further applications [131, 159-162].
The work is this area inspired Jensen and coworkers to
develop a simpler and faster pKa empirical prediction method
[163] implemented in the program PROPKA [164]. The
root-mean-square deviation (RMSD) of predicted pKa from
experimental values was found to be less than 1 [163].
PROPKA can also predict pKa for protein-ligand complexes
[165]. Once pKa of all ionizable sites are known, it is easy to
predict the protonation states for a given pH.
An alternative approach to computing pKa of amino acids
was proposed by Cui et al. [166], who combined QM/MM
with the free energy perturbation (FEP) method (QM/MM-
FEP). The thermodynamic cycle is different from that used
in QM/EFP. One of the most important differences is that the
Alexeev et al.
ionizable amino acid is directly transformed from the proto-
nated form into the deprotonated form with FEP. Thus, FEP
computes directly the difference of the solvent environment
interaction of the amino acid from the protonated form into
the deprotonated form. As a result this approach is more ro-
bust because the variations in the electronic structure and
nuclear geometry during the protonation of the amino acid
are computed accurately [167]. But there are disadvantages:
relatively high computational cost, the accuracy dependence
on a number of parameters, and having to treat multiple titra-
tion sites. But for certain systems such as proton pumps and
redox reactions [168] this is a promising approach.
The described QM/MM-FEP method was applied by Cui
et al. to compute pKa for CH3 CH2SH in water [166]. The
experimentally determined pKa is equal to 10.6 [169]. By
using the self-consistent charge-density functional tight bind-
ing (SCC-DFTB) model [170] and the water molecules de-
scribed by TIP3P model [171] the computed pKa was equal
to 7.7. In principle, SCC-DFTB can be replaced by a QM
method in GAMESS via the Q-Chem module in CHARMM,
which may improve the results.
5.2. Geometry Optimization
There are several options for geometry optimization of
large systems in GAMESS: IMOMM, QM/MM and FMO. It
is important to consider the level of accuracy, the cost of
calculations, the simplicity of computational setup and the
reliability of solvent models. In the following, we focus on
the use of FMO.
FMO can be applied to optimizations of biochemical
systems either in its usual form or with the frozen domain
(FMO/FD); in addition, there is an ongoing work [75] to
develop FMO/MM. For the regular FMO, where one treats
the whole system with FMO and optimizes the system using
the total energy gradient, the computational cost is aggre-
gated by the fact that most biochemical systems are very
flexible having flat energy surface, and require hundreds or
thousands of single point calculations if all degrees of free-
dom are optimized. We briefly mention without further dis-
cussion the existence of the problem of finding the global
minimum, and the need to sample other local minima, both
of which are of major concern when explicit models of sol-
vation are used.
The Trp-cage miniprotein (304 atoms) was optimized
with FMO using MM [75] or PCM [133, 134] to treat the
solvent. When the dispersion is included, a good agreement
to experiment is obtained: RMSD to NMR experiment was
0.414 Å [134]. In addition, the helical oligosaccharide hepa-
rin was also optimized in solution [172] (RMSD to NMR
experiment: 0.586 Å) and fluorinated prostaglandin receptor
was optimized in gas phase [173].
FMO/FD was developed to efficiently optimize an active
site in protein-ligand complexes. In this method, one takes
advantage of the fact that only atoms in the active site can
move during geometry optimization. Therefore, it is not nec-
essary to recompute the whole protein at each step. The
whole system is divided into the polarizable buffer Fig. (1D)
and frozen domain (the rest). The polarizable buffer includes
the active domain (e.g., the ligand and the binding pocket of
GAMESS for Drug Research
a protein) and it also includes some part of the protein sur-
rounding the active domain. This is done because the elec-
tronic state of the polarizable buffer should adjust to the
changes in the coordinates of the active domain.
FMO/FD does calculate the whole protein once for the
initial geometry at the level of FMO1, i.e., by self-
consistently polarizing all fragments in their total electro-
static field. For all consequent geometries, only the elec-
tronic state of the polarizable buffer is recomputed, in the
field of the fixed electronic state of the frozen domain. There
is a tracking of the movement of the polarizable buffer, so
that if necessary, one can recalculate the electronic state of
the frozen domain, or redefine the domains.
In addition to these direct cost reductions, one can further
improve the description by using a different basis sets and/or
wave functions for the frozen domain and polarizable buffer.
For the former, a very cheap level of RHF/STO-3G can be
used, while for the latter a better level of DFT-D/6-31G* can
be recommended (DFT-D is DFT with empiric dispersion).
This is the level used in the demonstrative optimization of
prostaglandin H(2) synthase-1 in complex with the reversible
competitive inhibitor ibuprofen (PDB: 1EQG), containing
19471 atoms, which was accomplished in 32 hours on 6
desktop computers using quantum mechanics for all atoms
[77].
FMO/FD calculation requires some user input to define
the domains. The pilot calculations [77] provided guidelines
based on the optimizations of the Trp-cage miniprotein com-
plexes with a neutral and charged ligand. The latter type re-
quires larger domains for the same level of accuracy, be-
cause the polarization is longer-ranged. FMOtools [138]
have a convenient interface to set up FMO/FD calculations,
including a script processing for an automatic pipeline
stream of ligands.
In comparison to QM/MM, FMO/FD describes the po-
larization of the outer (frozen) buffer, and does not need pa-
rameters for the ligand, whereas in case of MM the problem
of having to provide force field parameters for ligands can be
very complicated. It should be noted that QM methods in
general are quite unforgiving for poor initial structures,
which can happen when raw X-ray or NMR structures are
taken, resulting in divergence of SCF. Therefore, it is neces-
sary to prepare an initial structure of the receptor (protein),
which is relatively easy to do with force fields such as
CHARMM or AMBER. X-ray structures often have an in-
sufficient resolution with ambiguous binding poses, and
therefore a reliable optimization of these structures is neces-
sary.
Next, receptor structure can be docked with ligand using
one of the docking programs like Autodock [174], Autodock
Vina [175], Dock [176], GOLD [177, 178], FlexX [179],
FRED [180], Surflex [181], GLIDE [182, 183], and ICM
[184] to generate binding poses. There is a question of reli-
ability of the ligand docking by these protocols. It is con-
ceivable in future to develop QM-based docking, by either
rescoring the poses using FMO energy function or using
faster FMO methods such as FMO/FD to generate new
poses. The most promising poses can be optimized at a
higher QM level. This procedure can be repeated for multi-
Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 9
ple ligands. To understand the interaction mechanism of dif-
ferent ligands PIEDA can be a valuable tool. FMO/FD can
be used in other applications. For example, if an X-ray struc-
ture of a receptor-ligand complex is available at low resolu-
tion then FMO/FD can be used to optimize geometry of the
ligand.
6. DRUG DESIGN RELATED STUDIES
While force field applications to drug research in the
form of MM [2] and QM/MM [11] have been numerous and
fruitful, a number of researchers pointed out the advantages
of QM based approaches [185-188] in studying biochemical
systems or demonstrated the efficiency of quantum refine-
ment [189]. Fujimura and Sasabuchi argued that many com-
monly used force fields such as AMBER may not be reliable
for treating halogen atoms [173]. Ozawa et al. [190] dis-
cussed the role of CH- interactions in ligand recognition,
based on FMO calculations. Chuman and coworkers [191-
193] used FMO for QSAR-related studies.
Ishida et al. [194] discussed the collective catalytic de-
vice in the chorismate mutase catalyzed reaction, using
QM/MM and FMO calculations. DNA and estrogen receptor
interaction was analyzed with FMO by Watanabe et al.
[195]. Fluorescent proteins find various use in biology and
Mochizuki and coworkers [196] showed the efficiency of
FMO in describing the excited states of red fluorescent pro-
teins. Zwier and coworkers [197] demonstrated how PIEDA
can be used in analyzing amide stacking in
-polypeptides.
6.1. Use of FMO in Binding Energy Calculations, Pro-
tein-Ligand Interactions, and QSAR
FMO is a fully QM alternative to QM/MM calculations.
Here, we briefly introduce applications of FMO to protein-
ligand complexes. Two general types of studies can be
named. (a) Analysis of systems, for which the binding is
known experimentally, and it is important to analyze how the
ligand is recognized by the protein. This often gives hints to
possible mutations in the protein or to choose a different
ligand in order to increase the binding. In addition, a good
agreement to experiment can be used to justify the computa-
tional model. (b) Predicting the binding affinity of ligands,
for which no experimental data are available. This can be
used for screening ligands, and discovering new potent
drugs. FMO can be utilized for both of these study types.
Nemoto et al. [198] used multilayer FMO in studying
ligands bound to pheromone-binding protein. Nakanishi et
al. [199] elucidated the molecular recognition mechanism of
the FK506 binding protein by combining gas phase FMO
and solvation energies from MM models. Sawada et al. [200,
201] complemented FMO/PCM results for a single structure
with MM-derived entropic contributions in their analysis of
the binding between sialosides and influenza virus hemag-
glutinin. These studies clearly demonstrate that gas phase
calculations lead to a drastic overestimation of the binding
because of the desolvation penalty [202], i.e., the energy cost
to partially desolvate the protein and ligand surfaces during
their complex formation. Sawada et al. [200, 201] also dem-
onstrated that FMO can be applied to large size systems at
the solvated level with electron correlation (FMO-
10 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18
MP2/PCM/6-31G*): the protein-ligand complex treated at
this level contained 24060 atoms.
A by-product of the total binding energies with FMO is
the pair interaction energy analysis, which gives the inter-
fragment interaction energies, for example, between amino
acid residue fragments and the ligand. Here, some caution in
comparison to other methods such as MM should be exer-
cised, because fragment residues differ from conventional
residues by one carboxyl group, due to the electron delocali-
zation in the peptide bonds, as mentioned above. Using this
analysis, important insight on the ligand recognition can be
obtained. The total pair interaction energies can be further
decomposed into physical components in PIEDA, as de-
scribed above.
Ohno et al. [203] took advantage of PIEDA in their de-
tailed study of the binding of biphosphates to farnesyl pyro-
phosphate synthase. Merz et al. [204, 205] demonstrated that
FMO is efficient in predicting the native conformations of
proteins, and an even better prediction can be obtained with
parametrized corrections of the basis set superposition error.
Prime et al. [206] used PIEDA as a tool in their discovery
and SAR of potent and selective covalent inhibitors of trans-
glutaminase 2 for Huntington’s disease.
In classical QSAR studies the descriptors are often com-
puted using empirical formulas based on the structure and
the connectivity of atoms in the molecule. More accurate
electronic structure descriptors can be derived from QM cal-
culations using FMO, for example, the highest occupied and
the lowest unoccupied orbital energies. But FMO can also be
used to prove new kinds of descriptors to improve the accu-
racy of QSAR. For example, Chuman and coworkers [192]
suggested using CT and pair interaction energies between the
ligand and amino acids in the protein, as descriptors in
QSAR. Zhang et al. [207, 208] used FMO in the three-
dimensional quantitative structure-activity relationship (3D-
QSAR) combined with the comparative molecular field
analysis (CoMFA) to study receptor-ligand binding models.
6.2. FMO Applications in Drug Discovery
Accurate estimation of the affinity of a small ligand to a
macromolecule is extremely challenging. Many methods
have been developed to this end, ranging from rigorous but
time-consuming FEP and thermodynamic integration (TI)
simulations to fast empirical scoring functions. However,
even FEP and TI methods are only accurate within the limit
of the parameterization of the force field used. In recent
years, it has been reported that intermolecular forces that can
only be properly treated by quantum mechanical methods are
playing important roles in bimolecular interactions. For this
reason, in many occasions in drug discovery, it is highly de-
sirable to study the ligand/protein complex using quantum
mechanical methods. Such instances include but are certainly
not limited to:
• studying the electrostatic and dispersion profile of an
X-ray crystal fragment hit,
• during SBDD and FBDD when there is a requirement
to rationalize a SAR based on complex interactions,
Alexeev et al.
• assigning the optimal fragment binding pose present in
crystal structures for fragment-based drug discovery,
• decomposing a ligand into fragments to study the struc-
tural contributions to binding free energy,
• assigning the correct ligand binding pose amongst mul-
tiple similarly scored poses from virtual screening,
• predicting the correct binding pose in poorly resolved
X-ray crystal structure electron densities.
A challenge for computational chemistry support of in-
dustrial rational drug design efforts is to find the appropriate
balance between the level of complexity and the computa-
tional overhead required to understand drug-receptor interac-
tions within the timescale necessary to drive medicinal
chemistry. The highly parallelized FMO calculations using
the 6-31G* basis set with the second order Møller-Plesset
(MP2) perturbation method provide a practical solution to
achieve the required accuracy and speed. This moderate level
of theory in combination with the FMO methodology allows
for tens of calculations to be run per day on a relatively small
cluster (32 CPU cores and 3G of RAM per core) sufficient to
achieve the required accuracy and effective timescale to im-
pact medicinal chemistry projects related to the analysis of
protein-ligand interactions, although for massive screening a
much faster time scale is needed. The advantage of MP2
includes the ability to observe the dispersion type interac-
tions of aromatic and alkyl chains often seen in protein-
ligand interactions as well as halogen-
interactions which
are difficult to capture with MM force fields alone.
SARs can be analyzed and the design of new molecules
can be driven using the FMO methodology. This process is
optimal when the initial start-points for the calculations are
derived from X-ray crystal structures. The alternative
method to obtain starting points for ab inito calculations
would be to take an average structure over a number of mo-
lecular dynamics snapshots. Therefore an assumption is
made that the conformation of the X-ray crystal structure is
likely to contribute significantly to the Boltzmann-averaged
potentials for the free energy estimation. And that a single
point calculation is more likely to be a good representation
of the system than one from which the phase space is poorly
sampled. This method has been used previously to generate
poses for FMO calculations [209]. Other studies have used
MM/MD simulations ascertain an optimal system conforma-
tion before further analysis using FMO [210].
For example, FMO can then be used in a combinatorial
fashion to study the expansion of fragment- and lead-like
hits, to explore fragment merging, functional group replace-
ments and scaffold hopping via multiple calculations based
around a single crystal structure. Fragment linking strategies
can also be realized in circumstances where the receptor pre-
sents multiple distinct neighboring binding pockets and there
are fragments which occupancy a single or a number of these
sites taken from one or more crystal structures [211]. The
optimal fragment linking process will result in a compound
which has potency greater than the sum total of the individ-
ual fragments. This phenomenon is referred to as positive
cooperativity [212]. A recent review identified several ex-
amples of fragment linking in the literature [213]. This has
GAMESS for Drug Research
been demonstrated in the fragment linking of two Hsp90
fragments, 1 (IC50 = 1500
M) and 2 (IC50 = 1000
M), to
yield the more potent inhibitor 3 (IC50 = 1.5
M) [214], see
Fig. (2).
Fig. (2). The complex of fragments 1 (the left part of the ligand in
the center, shown in green) and 2 (the right part of the ligand in the
center, shown in cyan) bound together in Hsp90 (PDB ID: 3HZ1)
aligned to the crystal structure (PDB ID: 3HZ5) of the Hsp90 in-
hibitor 3 (yellow). (The color version of the figure is available in
the electronic copy of the article).
These results were supported by FMO analysis using
MP2 and the 6-31G* basis set in combination with PCM Fig.
(3). As calculated by the FMO method, linking fragments 1
(-8.87 kcal/mol) and 2 (-9.03 kcal/mol) via a propyl linker to
yield compound 3 (-41.3 kcal/mol) results in an increase in
binding energy [214]. In successful fragment linking there is
a requirement to maintain the thermodynamic profile of the
linking partners. This is analogous to optimizing the thermo-
dynamic signature in lead discovery [215]. Fragments which
are stabilized through H-bonds to the receptor (enthalpic
binders) and in addition can accommodate a degree of sub-
stitution are an attractive starting points for fragment expan-
sion [216]. Fragments which are bound through more hydro-
phobic interactions and tend to have a more entropic ther-
modynamic signature are ideal fragments to which an en-
thalpic fragment should be linked. This entropic signature is
associated with the hydrophobic effect of ligand binding.
Contribution of hydration to the thermodynamics of ligand
binding has been a topic of considerable interest for recent
years [217, 218]. It is generally understood that the major
energetic contribution to the hydrophobic effect during the
association of a ligand and its receptor comes from the re-
moval of high energy (unstable) water molecules from the
binding site and essentially entropic in nature. We believe
that the ligand/receptor interface with high dispersion inter-
action term identified by FMO PIEDA is very likely to be
associated with the presence of these high energy waters and
research to prove this hypothesis is currently ongoing. Hy-
drogen bonds have a large electrostatic energy term whereas
the dispersion energy term is the dominant attractive compo-
nent in hydrophobic interactions. The ratio of the electro-
static and dispersion energy terms to the sum of the pair in-
teraction energy results is a useful indication of the suitabil-
ity of a fragment for hit expansion see Fig. (3). PIEDA [90]
Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 11
allows these terms to be extracted from the FMO calculation,
as shown in Fig. (3). Fragment 1 has a larger electrostatic
contribution to the sum of the PIE than fragment 2, which
instead has a more dominant dispersion energy contribution.
Hydrogen bonds are highly directional thus when they are
formed between a fragment and a receptor they act as an
anchor to hold the fragment in place. This is in contrast with
fragments which bind through dispersion forces where mul-
tiple binding poses are often possible, as was observed for
fragment 2 where two crystal structures gave two different
binding poses [214]. As well as being very important infor-
mation in fragment linking, this is particularly useful in the
selection of fragments hits on which fragment expan-
sion/evolution will be proposed.
For protein-ligand interactions, particularly in the context
of drug discovery and guiding medicinal chemistry, the most
important pairwise fragment interactions are those between
the ligand and the protein fragments. Subtle changes in
ligand substituents can be studied using FMO in a con-
generic series of compounds which have well resolved crys-
tal structures. This has been demonstrated through the analy-
sis of 14 X-ray structures taken from the literature of CDK2
inhibitors [209]. Here, the sum of the PIE for the 14 inhibi-
tors correlated well (r2 = 0.68) with the free energy of bind-
ing as calculated from the measured potencies. This “SAR-
by-FMO” approach assumes that protein induced conforma-
tional changes upon the ligand modification are kept to a
minimum and that the only requirement is for proton re-
optimization. To speed up the calculations, solvation effects
are generally ignored. Although solvation and entropic terms
can be added in later, it is clear that FMO calculations can be
used in this simple manner, where optimizing primarily for
enthalpy is desired in pockets which are not too solvent ex-
posed. Sum of the PIE derived from FMO calculations can
then be used to rank order compounds and to help prioritize
compounds for synthesis.
In situations where speed is important, the additional
terms to treat solvation and entropy can be sought from other
means and combined with the enthalpic contribution from
FMO by performing partial least squares (PLS) regression on
the combined terms. This is particularly useful when the in-
dividual terms come from disparate methods, as the terms
can then be scaled appropriately. QSAR models built using
PLS can be used as scoring functions to predict ligand po-
tency. As an example, the calculation of ligand-binding free
energies was modeled using the FMO method to describe
enthalpic binding term, a polar solvation term described us-
ing Poisson-Boltzmann surface area (PBSA) techniques, a
nonpolar solvation term estimated from the solvent-
accessible surface area of the ligand and a ligand-based ro-
tatable bond count as a measure of conformational ligand
entropy [209]. A QSAR model was built using a training set
derived from the 14 CDK2 inhibitors which were structurally
solved. The resulting model was very predictive, with an r2
of 0.939 and a q2 of 0.896. This model was then used to pre-
dict a data set of a further 14 CDK2 inhibitors from the lit-
erature [219, 220] giving an r2 of the test set of 0.68 and a
root mean squared error of prediction of 1.00.
In an alternative procedure, a virtual library of com-
pounds can be built around a single crystal structure, and
allow the use of FMO in a predictive fashion, without the
12 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18
Fig. (3). Left: PIEDA for fragments 1 and 2. Showing the electrostatic term (Ees=
and mixing terms (Ect+mix= ) and the dispersion term (Edisp=
in (μM); dG, the free energy of binding at 298K; FMO+PCM, the binding energy calculated using FMO and the PCM water model;
ES/(D+CT), ratio of the electrostatic term over the sum of the dispersion and CT terms extracted from the PIEDA. (The color version of the
figure is available in the electronic copy of the article).
need for a QSAR model. In this procedure, the size of the
system to be calculated is kept minimum, i.e. typically the
ligand and only the surrounding amino acid residues, in or-
der to ensure reasonable throughput. If it is appropriate to do
so, only a part of a ligand, the R-group moiety which is to be
changed during a hit/lead optimization, can be included. This
technique is often used for initial fragment hit expansion or
for optimization of a congeneric series of compounds and
particularly effective for solvent inaccessible rigid biding
pockets as most of the energetic terms not accounted for by
FMO method tend to cancel out. We term this procedure
“SAR-by-FMO” and an example of this is presented below.
This method can also be useful for scaffold hopping and in
fragment replacement.
As an example, Wyatt et al. described the fragment-
based drug design against CDK2, starting from a number of
fragment hits, which were then crystallized [220]. One of the
resolved structures was the fragment hit (PDB ID: 1WCC),
entry 1 in (Table 1). This fragment has an activity of 64%
inhibition at 1mM. It was of initial interest as there are three
interactions formed between the fragment and the Hinge
region backbone of the CDK2 receptor along residues
Glu81, Phe82 and Leu83. These are depicted in Fig. (4), and
following the FMO convention of fragmentation are labeled
Phe-82, Leu-83 and His-84, respectively. An interaction that
was not thoroughly examined in the literature is that formed
between the chloro substituent and the gate-keeper Phe80
residue, which contributes to about 5 kcal/mol of energy. At
the MP2/6-31G* level of theory the interaction can be ob-
served as being a combination of dispersion and CT energy
terms. This is likely as the chloro group has a positively
charged  hole which is likely to interact with the electron
rich
-system of Phe-80 [221], an interaction which is poorly
represented in MM force fields and often overlooked. Al-
though it is also reasonable to assume that the chlorine atom
may be replacing a high energy solvating water molecule
which might exist in this part of the biding pocket, the con-
tribution from this type of halogen-
interaction cannot be
ignored. The authors attempted to change the chloro sub-
stituent for alternate functional groups without success and
consequently the series was dropped.
Alexeev et al.
), the exchange repulsion term (Eex= ), the CT
), energies are in kcal/mol. Right: Table showing the activity
In order to demonstrate the usefulness of “SAR-by-
FMO” approach we have compiled a small virtual (except
compound 13 which was actually synthesized in the work)
library of 1WCC ligand analogues (Table 1) and their FMO
interaction energies calculated Fig. (5) so that the effect of
substituent changes on binding free energy can be predicted.
Replacing the chloro (entry 1 Table 1) for a fluoro (entry 2),
proton (entry 3) or methyl group (entry 12) all result in a loss
in binding energy, similarly, entries 4, 5 and 7. This suggests
that the chloro is necessary for activity. Further changes to
the ring system, pyrazine to pyridine (entry 11, Table 1)
could be demonstrated by FMO to be less favorable changes.
However, substituent changes to the amino group could offer
further gains in potency. Indeed, the authors went on to pre-
pare compound 13 (Table 1) which had reasonable activity
(IC50 = 7 μM). Using the “SAR-by-FMO” approach con-
firms this approach with a favorable change in binding en-
ergy. This analysis reveals that there are other scaffolds that
could have also been interesting fragment hits for further
investigation, including entry 6, 9 and 10 (Table 1), all of
which have increased binding interactions to the receptor
compared to the 1WCC fragment hit.
FMO can have particular utility in understanding protein-
protein interaction (PPI) targets. FMO is extremely powerful
in quickly identifying important structural features around a
moiety and for quickly establishing virtual SAR to prioritize
compounds prior to synthesis. This is a suitable method for
FBDD and for small sub-structural changes which are not in
conjugation to a larger parent ligand. As well as fragmenting
proteins into amino acid monomers, large ligands can also be
fragmented across single bonds. This is particularly useful in
the modeling of peptide mimetics to target protein-protein
interactions or peptide substrate receptors, for example, in
the structure-based design of peptide-like, type-1, renin in-
hibitors to treat primary hypertension [222]. Here, potent in
vitro inhibitors, like CGP 38’560, mimic the binding mode
of the endogenous renin substrate angiotensinogen, Fig. (6).
These large compounds suffer from a high molecular weight
and high lipophilicity leading to poor oral absorption and
rapid biliary uptake. Rahuel et al. reported the optimization
of renin inhibitors by truncating the large peptidomimetic to
GAMESS for Drug Research Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 13

Table 1. SAR-by-FMO. Fragment Analysis Using FMO to Calculate the Total Sum of the Pair Interaction Energies (PIEs)

Entry PIE (kcal/mol)

R1 N R2

A R1 R2

1 -21.44 N Cl NH2

2 -20.13 N F NH2

3 -20.23 N H NH2

4 -20.00 C H NH2

5 -21.07 C CH3 NH2

6 -22.53 N Cl H

7 -21.32 N H H

8 -21.13 N Cl OCH3

9 -24.20 N Cl NHCOCH3

10 -24.06
Cl N

11 -21.10 C Cl NH2

12 -21.06 N CH3 NH2

13 -23.03 N Cl NHPh

Fig. (4). FMO analysis of 1WCC. A) PIEDA for Entry 1 Table 1 (PDB ID: 1WCC) showing the electrostatic term (Ees), the exchange repul-
sion term (Eex), the CT and mixing terms (Ect+mix) and the dispersion term (Edisp), energies are in kcal/mol. B) pair interaction energies
(PIEs) for each of the amino acids neighboring the fragment, showing attractive and repulsive energy contributions in kcal/mol. C) Depiction
of the fragment within the CDK2 binding pocket, taken from the PDB ID: 1WCC [10]. (The color version of the figure is available in the
electronic copy of the article).
14 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 Alexeev et al.

Fig. (5). Plot of the difference in pair interaction energies (PIE) from 1WCC. Graph showing the difference in the total sum of the PIEs be-
tween fragment 1 ( Entry 1, Table 1) and 12 other fragments from Table 1. Fragments which have enhanced binding interaction energy as
compared to fragment 1 are shown as blue bars pointing downwards (with negative energy differences). (The color version of the figure is
available in the electronic copy of the article).

Fig. (6). X-ray structures of peptidomimetics and fragmentation scheme used in the FMO analysis. Left: Top: CGP 38’560 (PDB ID: 1RNE);
middle: compound 7 (PDB ID: 2V13); bottom: Aliskiren (PDB ID: 2V0Z). Right: The corresponding fragmentation scheme used during the
FMO calculations. (The color version of the figure is available in the electronic copy of the article).
GAMESS for Drug Research Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18 15

improve ligand efficiency and physiochemical properties
resulting in the discovery of Aliskiren [222]. With the avail-
ability of the X-ray structure of CGP 38’560 [223] and its
analogues [222], FMO can be used to examine these struc-
tures in greater detail. Using FMO, CGP 38’560 can be
fragmented into 4 components and the contribution of the
fragments to the total sum of the PIE can be determined, Fig.
(6) and (Table 2). An examination of the fragment PIEs re-
veal that fragment B contributes nearly half of the total PIE.
A measure of the fragment efficiency, FE, can be calculated
by dividing the fragment PIE by the fragment heavy atom
count,
Fragment Efficiency = Pair Interaction Energy / Heavy Atom
Count (7)
These few case studies demonstrate how FMO can pro-
vide important information on the nature of protein ligand
interactions to support medicinal chemistry projects. In par-
ticular the importance of the total sum of the PIE was men-
tioned as a means to establish “SAR-by-FMO”. The analysis
of fragment contributions via the fragment efficiency, FE,
metric provides alternative means to prioritize compounds
for further investigation. In addition, the results from FMO
can be presented in a visually meaningful fashion. The appli-
cations demonstrated here were run using FMO as a single
point calculation. Work is ongoing to establish whether
FMO/FDD can be developed into a routine method for
SBDD to assess ligand protein interactions to calculate the
free energy of binding at a greater level of accuracy.

Fragments A, A’ and C have a reduced percentage con- 7. CONCLUSION AND OUTLOOK

tribution to the total PIE, and fragments A and B have low
FEs, indicating inefficient receptor binding for these frag-
ments. In the course of the development compound 7 was
identified as having improved oral absorption in vivo [222].
This compound has an overall larger FE compared to CGP
38’560 despite the removal of the S2 pocket moiety. This
compound was fragmented similarly to CGP 38’560, Fig.
(6). The marked size reduction of fragment B (FE = 5.71),
CGP 38’560 (FE = 4.78), and the greatly improved binding
of fragment A to the receptor via the S3sp sub-pocket (FE =
4.10), CGP 38’560 (FE = 1.71), contributed to the improved
binding efficiency of this compound Fig. (6). The reduction
in potency is calculated by FMO to be due to the reduction in
attractive binding for fragment B. Performing the same
fragmentation on Aliskiren and running the FMO method on
this compound showed how potency was regained in this
clinical candidate. Here, there was an improvement in the
PIE, (PIE = 83.95 kcal/mol), together the FE of fragment A
being retained, to give an overall increase in PIE for the
ligand.
The FMO and QM/MM methods are reliable computa-
tional tools, and the advances in both hardware and software
development have made these calculations practically avail-
able to end users. It seems that in part the reason for a rela-
tively minor overall use of QM in drug design is the inertia
on the part of computational scientists, and it is our hope to
raise the interest to QM methods in drug discovery commu-
nity with this review.
Clearly, QM methods offer major advantages over other
approaches, and the difficulty is in selecting the right method
for a given problem. In many cases, especially, when the
dynamic (entropic) factor is of major importance, it is con-
ceivable that traditional MM approaches combined with mo-
lecular dynamics will continue to be used for those studies.
QM methods have a potential to become a primary tool in
many areas of drug design, especially in designing ligands
with high affinity and specificity, because now one can af-
ford to use these more expensive but also more accurate ap-
proaches in actual drug research.

Table 2. Fragment Efficiency (FE). Examination of the Fragment Contributions to the Total Pair Interaction Energies (PIE) for
the Peptidomimetics CGP 38’560, Compound 7 and Aliskiren. Showing the Activity in μM, the Total PIE and Total FE
As well as the Fragment Contributions to PIE and FE and the Percentage (%) of the Total Contribution to the Ligand
PIE. See Figure 5 for the Fragmentation Scheme

Total PIE (kcal/mol)

Compound Activity (μM) Fragment PIE (kcal/mol) % of total PIE FE
[Total FE]

A -27.40 15.5 1.71

A’ -28.43 16.1 2.84

CGP 38’560 0.001 -176.63 [3.46]
B -85.98 48.7 4.78

C -34.84 19.7 4.98

A -65.62 43.1 4.10

7 0.022 -152.28 [4.61] B -57.11 37.5 5.71

C -29.55 19.4 4.22

A -51.47 26.9 3.43

Aliskiren 0.0006 -191.11 [4.90] B -83.95 43.9 6.00

C -55.69 29.2 5.57

16 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 18
In this review, we have shown how the methods imple-
mented in GAMESS program suites can be used in realistic
studies of biochemical systems, in particular, FMO and
QM/MM. We have also briefly introduced various user inter-
faces taking care of the technical issues in setting up input
files and visualizing the results. We hope that GAMESS will
find its increasing use in drug research.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
YA and DGF thank their former PhD supervisor Prof.
Mark S. Gordon and a long time mentor Dr. Michael W.
Schmidt, for their lifetime commitment to GAMESS-US
development and countless fruitful discussions. YA work is
supported by the Office of Science of the U.S. Department of
Energy under contract DE-AC02-06CH11357. DGF thanks
Prof. Kazuo Kitaura for many insightful discussions and
acknowledges partial financial support from the Next Gen-
eration Super Computing Project, Nanoscience Program
(MEXT, Japan) and Strategic Programs for Innovative Re-
search (SPIRE, Japan). We also thank Dr. Alex A. Gra-
novsky for his comments on Firefly. OI and MM thank Dr.
Mark Whittaker and Dr. Richard Law for many inspiring
comments and support.
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Received: May 11, 2012 Revised: July 30, 2012 Accepted: September 06, 2012
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