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org/jcim Article

DLPGEN: Preparing Molecular Dynamics Simulations with Support

for Polarizable Force Fields
Carlos E. S. Bernardes*

Cite This: J. Chem. Inf. Model. 2022, 62, 1471−1478 Read Online

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ABSTRACT: Preparing input files for molecular dynamics (MD)

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simulations can be a tedious task, particularly if different MD

programs need to be used. Most simulation packages are
accompanied by applications that handle this task, and, in some
cases, software to perform interconversion between MD programs
can be found. However, the conversion between different types of
files is not always foolproof or the force field may not be fully
supported, as quite often observed with polarization models. This
work describes the program DLPGEN, which produces input files
for the MD programs GROMACS, CHARMM, DL_POLY, and
LAMMPS. The program can prepare polarizable force fields using a self-consistent field approach or with a dual thermostat-extended
Lagrangian model. For GROMACS, a new polarization scheme suitable for the simulation of molecules containing more than one
virtual particle is described. Results obtained for ethanol in the liquid state revealed that the system configurational energy, liquid
density, and self-diffusion coefficient obtained with GROMACS are in good agreement with the data found with LAMMPS and
CHARMM. In the case of DL_POLY, a problem with the Shells temperature control was found, suggesting that this program may
not be suitable for the simulation of molecules containing multiple Drude particles.

1. INTRODUCTION large time scales.12 Consequently, because it may be extremely

One of the key steps to run molecular dynamics (MD)
simulations involves the production of input files that are fed
into the main simulation packages. In general, this requires a
cross-check between different types of data, like molecular
structure (e.g., atomic coordinates) and force field para-
metrizations, to generate a set of formatted files that are
readable by the MD software.1,2 Unfortunately, different coding
procedures are used by different MD programs, so that, except
for a few cases, no transferability of input files exists.
Most simulation programs are accompanied by applications
that handle the task of preparing the input files. However,
because each MD application has its abilities and limitations, a
user can find itself in the need to use more than one program to
tackle different problems. For example, (i) DL_POLY is, most
likely, one of the most robust programs for the simulations of
crystal structures;3−6 (ii) LAMMPS is one of the more versatile
MD software, with the support of a large variety of force fields
and features;7,8 (iii) for the use of polarizable models, because of
the extensive developments over the last decades, CHARMM is,
most likely, one of the most robust programs to run simulations
using the classical Drude oscillator model;9−11 (iv) although
rather limited in terms of supported force fields and simulation
options (e.g., a limited number of barostats, thermostats, and
interaction potential functions are available), GROMACS is,
probably, one of the fastest free MD programs, making it ideal to
perform the simulation of extremely large systems or to tackle
difficult for a user (particularly one at the beginners level) to
learn the tricks of the trade of new software, applications that can
facilitate this transition are in demand. Programs like
FFTOOL,13 ForConX,14 CHAMBER,15 and MDWiZ16 have
been developed over the years, aiming at the creation and
interconversion of input files between different platforms.
However, using these applications, it may be difficult to obtain
input files from scratch, some are not bidirectional, and 100%
transferability is not always ensured during the conversion
process.
The program DLPGEN, which dates from 2015,4 was initially
developed to produce input files for DL_POLY using force fields
based on the all-atom optimized potentials for liquid simulations
(OPLS-AA) and polarization using a scheme similar to the
classical Drude oscillator method.17 A later upgrade enabled the
production of GROMACS input files. However, because of the
poor documentation on how to implement polarization in this
program (particularly for molecules with several polarized
Received: December 18, 2021
Published: March 3, 2022

© 2022 American Chemical Society https://doi.org/10.1021/acs.jcim.1c01431

1471 J. Chem. Inf. Model. 2022, 62, 1471−1478
Journal of Chemical Information and Modeling pubs.acs.org/jcim Article

Figure 1. Schematic representation of the program DLPGEN.

atoms), this option was left aside. From these initial steps, it and crystal unit cell dimensions. The GEN file contains the
became clear that DLPGEN had the potential to become a atomic coordinates of the atoms for a given molecule and
capable platform to prepare input files from scratch for a larger additional instructions necessary to set the force field. These
variety of MD simulation programs. In addition, if the produced include (i) virtual particles details; (ii) definition of rigid units;
input files follow a similar structure, a significant decrease in the (iii) polarization details; and (iv) symmetry operations to build
“activation energy” for the use of different MD software could be crystal structures. Finally, the LIBrary file contains the force field
achieved. Thus, this work describes the most recent develop- data in the form of the potential function, Ucfg:
ments to this program, which include (i) support for DL_POLY, bonds angles dihedral
GROMACS, LAMMPS, and CHARMM; (ii) support of Ucfg = ∑ Ubonds + ∑ Uangles + ∑ Udihedral
polarizable models for all MD packages (for this, a “new” ij ijk ijkl
implementation scheme for the treatment of polarization in
GROMACS is described); (iii) ready-to-go input files, with + ∑ ∑ Ucoul + ∑ ∑ Uvdw
similar structures independent of the destination software (as far i j>i i j>i (1)
as it is possible), from which the user can easily set new
In the previous equation, Ubonds and Uangle represent the
simulations and explore the features of the different MD
potential functions that describe the motion of the bonds and
programs.
angles of a molecule, respectively, as harmonic oscillators:
This study has the following structure. Initially, a brief
overview of the DLPGEN program is given. Next, a small review k r, ij
of polarizable force fields is presented, with a discussion of the Ubonds = (rij − ro, ij)2
2 (2)
corresponding implementation for each MD program. Finally, a
comparison of simulation results obtained using the different kθ , ijk
programs is provided. Uangles = (θijk − θo, ijk)2
2 (3)

2. DLPGEN PROGRAM
One of the difficulties in the development of an application that
interconverts input files is to ensure the compatibility between
the potential functions that can be used with each MD program.
Some of these problems, dealing with, for example, energy and
distance units, can easily be handled. However, not all force
fields models and algorithms are supported by a given software.
Good examples are the implementations of polarization models,
the ability to recognize virtual particles, or the supported
barostats and thermostats. Thus, a program that can create input
files for multiple MD packages must be able to automatically
account for these issues.
A schematic representation of the DLPGEN program is given
in Figure 1. The program requires three types of files to run: a
program control file (PCF), a GENesis file, and a LIBrary file.
The PCF contains information about the system to be
simulated, as the molecules to be used, simulation box size,
1472
where rij and ro,ij are the distance and the equilibrium distance
between atoms i and j, respectively; θijk and θo,ijk are the angle
and equilibrium angle between atoms i−j−k. In turn, Udihedral
represents the variation of the potential energy of a dihedral as a
function of the angle φijkl defined between atoms i−j−k−l. In
this case, it is possible to use one of the following functions for
each dihedral:
4
Vn , ijkl
Udihedral = ∑ [1 + ( −1)(n − 1)cos(nφijkl)]
2 (4)
n=1
Udihedral = K ijkl[1 + cos(mφijkl − f )] (5)
where Vn,ijkl are Fourier constants, Kijkl is the dihedral coefficient,
m is a non-negative integer coefficient that sets the number of
nodes of the cosine function, and f is the dihedral phase. Eq 4 is
also used to define the improper dihedrals, by setting V1 = V3 =
V4 = 0 and V2 > 0.
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The Coulomb, Ucoul, and van der Waals, Uvdw, functions in eq
1 are based on the classical electrostatic and 12-6 Lennard-Jones
relations:
qiqj
Ucoul =
ÅÄÅ ÑÉ
4πεorij (6)
ÅÅij σ yz12 ij σ yz6ÑÑÑ
ÅÅjj ij zz Ñ
= 4εijÅÅÅjj zz − jjjj zzzz ÑÑÑÑ
j
ÅÅ rij z j r Ñ z
ÅÅÇk { k ij { ÑÑÖÑ
ij
Uvdw
(7)
where εo is the vacuum permittivity, qi and qj are the atomic
point charges of atoms i and j, respectively, and σij and εij are the
Lennard-Jones parameters.
By default, the program follows the OPLS-AA18 force field
scheme, namely, (i) within the same molecule, the electrostatic
and van der Waals interactions between atoms separated by
three bonds (1−4 interactions) are scaled by a 0.5 factor
(different scaling factors can be used), (ii) the interaction
between atoms connected by one or two bonds are ignored, and
(iii) all bonds with hydrogen atoms are constrained. The LJ
parameters between different types of atoms can be computed as
geometrical means, applying Lorentz−Berthelot mixing rules
(sigmas computed as arithmetic means and epsilons as
geometric means), using custom LJ parameters for crossed
interactions, or the n−m potential function introduced by Clarke
ÄÅ mÉ
ij r yz ÑÑÑÑ
and Smith:19
Å
Eo ÅÅÅ ijj ro yzz
ÅÅmjj zz − njjj o zzz ÑÑÑ
n − m ÅÅÅ jj rij zz jj r zz ÑÑ
n
ÅÇ k { k ij { ÑÑÖ
Uij =
(8)
where n and m are the repulsive and attractive coefficients,
respectively, and Eo and ro are the energy and distance
parameters, respectively. By using the set of potential functions
described above, DLPGEN can, therefore, be used to set
simulations using force fields like OPLS-AA, CL&P, AMBER,
and CHARMM.18,20−23
When the program runs, the contents of the files are analyzed,
and the connectivity (bonds) between all atoms included in each
GEN file is determined. For this, the program compares the
distance between every two atoms against typical values for a
given type of bond. The current version of the program contains
a database with connectivity criteria for several atom pairs,
suitable to handle most of the common bonds observed in
organic compounds. Still, if a distance criterion to establish if
two atoms are bonded is not in the list, the program requests the
user for a reference value. In principle, the program can be used
with molecules containing an unlimited number of atoms, so
that any molecule (organic or inorganic) can be handled by
DLPGEN. After this process, the program determines all angles,
dihedrals, and improper dihedrals for the molecule. The
improper dihedrals are considered if (i) the central atom is a
carbon atom and is bonded to any three atoms (sp 2
hybridization); (ii) the central atom is a nitrogen (N) bonded
to three atoms (X) and if the angle defined by the improper
dihedral X−N−X−X is close to 0° or 180°.
The output files for a given MD package consist of at least
three files (see details below): (i) the first one contains the
topological details of the different molecular types in the system.
This file is compiled by linking the computed connectivity
information with the parametrization included in the LIB file;
(ii) the second file contains the initial positions of the atoms in
the simulation box; and (iii) the last one contains initial default
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simulation conditions to be used during a simulation (e.g.,
number of steps, timestep, cutoffs, temperature, and pressure).
The initial simulation box can be prepared using two
procedures: (i) by stacking small virtual boxes containing the
molecules or (ii) using the program PACKMOL24 (which
allows for the random distribution of the molecules inside a
simulation box). For the first procedure, several small boxes
(e.g., 10 Å × 10 Å × 10 Å), each one containing one molecule,
are staked to form an expanded cubic simulation box.
Alternatively, the unit cell of a crystal structure can be used as
a starting point, and by applying the symmetry operations of a
given space group to the corresponding asymmetric unit, a
perfect crystal structure for a given compound can be prepared.
The use of PACKMOL is integrated into DLPGEN, so only the
simulation box dimension or a target system density needs to be
provided by a user (for this, PACKMOL should have been
previously installed in the computer).
Full details on how to install, prepare the input files, and run
DLPGEN can be found in the manual that accompanies the
program or downloaded from https://bit.ly/3rIaSXu. Addition-
ally, a tutorial with a step-by-step description of how to use the
program is available on the YouTube channel DLPGEN
(https://bit.ly/3oLOESC).
3. POLARIZATION MODELS
The use of polarizable force fields has received significant
attention in recent years as it potentially enables a more accurate
description of the computed physical properties of substances
when compared with classical simulations. For example, (i)
when employed in the study of ionic liquids, it allows for a better
agreement between theoretical and experimental dynamic
properties data (e.g., diffusion data),25−27 (ii) when used to
investigate materials in the solid state, it allows for a better
agreement between experimental and computed energetic and
structural results of organic compound polymorphs,4 and (iii)
allows for a better description of carbon-based materials, like
graphene sheets and carbon nanotubes, with other substances.28
It should be mentioned, however, that MD simulations using
polarizable models come with a penalty in computation time
and, in some cases, for example, double counting of induction
and dispersion interactions may make the agreement of
simulation results with the experiment difficult.27,29 Detailed
information about the different approaches to include polar-
ization in MD simulations can be found elsewhere.17 Thus, in
this work, only a brief overview of the classical Drude oscillator
model (CDO) and the implementations used by DLPGEN is
discussed.
In the CDO model (Figure 2a), polarization is introduced by
placing virtual charged particles, β, (Drude or Shells) that move
around the atom Core, i. This configuration can be envisioned as
an electron cloud that reacts with the surrounding electric field.
The particle is connected by a spring to the atom nucleus,
allowing for the development of induced dipoles. The charge in
the Drude particles, qβD, is computed as follows:
qβD = 4πεok Dα (9)
where α is the atom polarizability, and kD is the force constant of
the spring connecting the Drude particles to the atom Core,
assuming a harmonic oscillator with an equilibrium distance of
zero:
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Figure 2. Schematic representation of the (a) classical Drude oscillator
model implemented in DLPGEN for the MD packages CHARMM,
LAMMPS, and DL_POLY, and (b) GROMACS.
D
k 2
U= ·riβ
2 (10)
where riβ is the distance between the Drude and the atom Core.
In general, two procedures are followed to set qβD and kD:17,25 (i)
the charges of the Drude particles are predefined, for example,
−1 e, and kD determined using eq 9; (ii) kD is fixed to a constant
value, typically between 4184 and 8368 kJ mol−1, and the
corresponding qβD value computed from eq 9. Although both
approaches lead to equivalent results, the latter one is normally
preferred, as it allows for better control over the timestep used in
the calculations. Finally, once qβD has been defined/determined,
the charge of the atom Core, qiC, is computed as follows:
qi C = q FF − qβ D (11)
where qFF is the charge of the atom type in the reference force
field.
The inclusion of virtual particles in the model leads to a
problem regarding the description of their dynamic motions.
Two main approaches were developed to address this issue: (i)
the Shells do not have mass, so after moving all atoms in the
simulation box, the position of each particle is recomputed to
minimize the energy/forces. For this, a self-consistency field
(SCF) approach is used to relax the Shells while keeping the
atom Cores at fixed positions, in a procedure that falls in analogy
to the Born−Oppenheimer approximation;30,31 (ii) a small mass
(typically mD = 0.4 amu) is transferred from the atom Core to
the Drude, enabling the inclusion of these particles during the
integration of Newton’s equations of motion.25,32 The latter
approach has the advantage of being faster because SCF
calculations are time-consuming and need to be run in every
simulation step. However, because the mass of the Drudes is
small, the timestep used in the simulations needs to be small.
This effect can be minored using the extended Lagrangian
approach developed by Lamoureux and Roux.33 By this way, a
dual thermostat is used in the simulation runs: the first one keeps
the atoms at the desired temperature and the second maintains
the Drudes at a very low temperature (e.g., ≤1 K). The
combined use of mD = 0.4 amu and a fixed spring constant force
of kD ≥ 4184 kJ mol−1 often allows for the use of 1 fs simulation
timestep.
An additional problem that can be found in the extended
Lagrangian approach, which is not an issue for the SCF method,
is the polarization of light atoms (e.g., hydrogens). Thus, quite
often, these atoms are not polarized in the force field, and the
corresponding polarizability is added to that of the heavy atom
they are attached to.25,26 In addition, if the molecules to be
polarized are ions, corrections to the polarizability of the cations
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(αe = −1.87 Å3) and anions (αe = +1.87 Å3) can also be included
in the force field, by evenly distributing this excess polarizability
throughout all atoms.34
When two adjacent Drude/Shell particles (in the same or
different molecules) are close to each other, a strong interaction
can develop. This may lead to an excessive energy variation,
causing unstable simulations and/or excessive correlation
between induced dipoles. To avoid this, a Thole screening
ÄÅ ÉÑ
function is employed:35,36
Å ij y ÑÑ
qiq j ÅÅÅÅ j z
zzz·e−a·rij /(αiαj) ÑÑÑ
Ñ
ÅÅ1 − jjj1 + z ÑÑ
rij ÅÅÅ jj 2(αiαj) zz
a · r
ÑÑ
ij 1/6
ÅÇ k { ÑÖ
Sk(rij) = 1/6
(12)
where qi and qj are the charges of the Drude/Shell/Core
particles that compose the induced dipoles, αi and αj are the
polarizabilities of the atoms, and a is the Thole damping
parameter. In the simulation of organic-based substances, the
latter constant is normally assumed to be equal to 2.6.36 When
Thole screening functions are not available in the MD package in
use, as an alternative, it has been proposed the application of
exclusion list between the induced dipoles separated by one or
two bonds and using scaling between atoms separated by three
bonds. This approach mimics the procedures used to handle
intramolecular Coulomb and LJ interactions between bonded
atoms. Although this does not scale the intermolecular
interaction, it was found to be suitable, for example, when
simulating ionic liquids using the CL&P force field.37,38
4. FORCE FIELD IMPLEMENTATIONS
This section gives a brief overview of the output files produced
with DLPGEN, with emphasis on the polarization methods
implemented for the different MD programs. By default, ready-
to-go files are generated, allowing for the simulation of a
molecular system under the NPT ensemble approximation, at
298.15 K and a pressure of 1 bar. If the simulation to be run
corresponds to a crystalline material, an NσT ensemble is
configured instead, by setting an anisotropic barostat. With the
exception of GROMACS, which uses a Parrinello−Rahman
barostat, a Nosé−Hoover barostat and a thermostat are defined
for the simulations. Independent of the program to be used, no
initial velocities for the particles are computed, a cutoff of 1.5 nm
with Ewald corrections is configured, and a timestep of 1 or 2 fs
is set.
4.1. CHARMM. For the simulations with CHARMM, four
files named “config.crd,” “parameters.prm,” “topology.rtf,” and
“input_chrm.inp,” are produced, which contain the initial
system configuration, the force field details, the molecular
information, and the simulation setup conditions, respectively.
The latter file is written in a scripting language, which makes
CHARMM extremely versatile. To simplify the setting up of the
simulations, the first lines of this file contain a “nonstandard”
section, where all main simulation variables can be easily
changed (e.g., temperature, pressure, timestep, cutoff, and
experiment number).
Arguably, from all programs supported by DLPGEN,
CHARMM is a reference for the implementation of the classical
Drude oscillator model. The setting up of polarization follows
strongly the CDO model described in the previous section.
4.2. LAMMPS. For the simulations with LAMMPS, three
files are produced, named “data.lmp,” “pair.lmp,” and “in.lmp.”
The first one contains the force field and initial configuration
data and the second the van der Waals interaction parameters.
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Like CHARMM, the file “in.lmp” uses a scripting language
approach to set up the experiments. Thus, the first lines of this
file also contain a list of variables that allow for an easy
modification of the simulation conditions.
The classical Drude oscillator model was recently developed
and included in the stable releases of LAMMPS by Padua and
Dequidt.39 The authors developed a Python tool named
“polarizer,” which can modify previously existent input files to
include polarization. Still, using this program, several simulation
details (e.g., thermostat configurations) need to be manually
added to run the simulations. The code implemented in
DLPGEN produces ready-to-go files that strongly follow the
classical Drude oscillator method described in Section 3.
4.3. GROMACS. For the simulations with GROMACS, three
files are produced, named “CONFIG.gro,” “topology.top,” and
“NPT.mdp.” These files contain, respectively, the initial system
configuration, the force field and molecular information, and the
conditions for the MD run.
In this work, it was found that the available information for the
implementation of the Drude oscillator model was extremely
scattered, particularly, if molecules containing more than one
Drude particle were considered. In 2015, Mackerel’s team40
released a GROMACS version supporting the classical Drude
oscillator model. As an example, the authors demonstrated how
to implement this force field for water. However, to the best of
my knowledge, this version of the program was never tested with
molecules containing multiple Drude particles, and the
implementation was never included in subsequent official
versions of GROMACS. Thus, in this work, an attempt to
implement a polarizable model suitable for use in the most
recent versions of the program was made.
As referred above, one of the key points of the extended
Lagrangian approach is the use of two thermostats, one for the
Core atoms and the other for the Drude particles. GROMACS
has built-in capabilities to set several independent thermostats;
however, to work properly, the temperature difference between
the two thermostats should be small (ca. <100 K). As a result, it
is not possible to use this approach if, for example, the Core
particle temperature is set to 298 K and Drudes at 1 K. This was,
in fact, one of the developments made in Mackerel’s work.40
To circumvent the previous issues, massless virtual Shell
particles were set, and the built-in force minimization algorithm
was used to compute the positions of each Shell at every step.
This implementation revealed, however, that when a molecule
contains atoms separated by three bonds, a catastrophic event
would rapidly occur. For example, in the case of the ethanol
molecule (Figure 2), the hydrogen atom of the hydroxyl group
can strongly interact with the Shell particle in the adjacent
methyl group. It was also found that the use of Thole screening
functions or hyperbolic spring constants, in this case, did not
avoid this process. This suggested that the latter models/
corrections are not appropriate to avoid catastrophic events
when massless Shells and force minimization methods are used.
This led to the following implementation (Figure 2b): (i)
each heavy atom has attached a massless Shell particle with
charge qβD; (ii) additionally, to each atom Core, a second virtual
particle located at the atom nuclei with charge −qβD was also
added (this particle does not move relative to the atom Core);
(iii) the charge of the atom Core is set to qFF; (iv) all interactions
between Shells and between the pair atom Core/virtual particles
for atoms separated by 1 to 3 bonds were added to the
interaction exclusion list; (v) Thole screening functions were
included in the model. The implementation of step iv allows for
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avoiding the catastrophic events described above while ensuring
the correct 1−4 Coulomb interactions between the atom Cores
(the only electrostatic interaction considered between atoms
separated by three bonds). Thus, the dihedral potentials are, in
this case, modeled exactly with the same potential functions of
the original force field (e.g., scaling the 1−4 interactions to 0.5,
as in the case of OPLS-AA and CL&P).18,21
4.4. DL_POLY. For simulations with DL_POLY, three files
named “CONFIG,” “FIELD,” and “CONTROL” are produced,
which include the initial system configuration, the force field and
molecular information, and the simulation conditions, respec-
tively. This MD program allows running simulations using both
the extended Lagrangian and SCF approaches. In the most
recent version of DL_POLY, it is also possible to use Thole
screening functions in the simulations with polarizable force
fields. Still, after several attempts and messages exchanged with
the developer of this module, no stable implementation of this
feature was obtained for molecules containing more than one
Drude/Shell particle (this will be pursued in future versions of
DLPGEN). The final implementation follows the CDO model
described in Section 3 using an exclusion list to ignore
interactions between atoms separated by one or two bonds
and with the interactions (Core−Core; Core−Drude; Drude−
Drude) separated by three bonds scaled by a factor of 0.5.
5. SIMULATION RESULTS
In this section, a direct comparison between MD simulation
results obtained using different software packages and input files
directly produced with DLPGEN is presented. Particular
attention is given to the results found using GROMACS with
a polarizable force field because of the novelty of the approach
described in this work. The tests consisted of the comparison of
simulation results for ethanol.
As a starting point, a simulation box with 600 ethanol
molecules was initially prepared and equilibrated using
GROMACS and considering the OPLS-AA force field.18 For
this, the following procedure was followed: (i) 2 ns MD run at a
temperature of T = 398.15 K and pressure p = 100 bar; (ii) 2 ns
simulation at T = 298.15 K and p = 100 bar; (iii) 3 runs at T =
298.15 K and p = 1 bar, with 5 ns each. The final simulation box
(which presented a constant density and configurational energy
in the last MD run) was then used as the starting point to prepare
the configurational files for each probed MD program. Before
each production stage, an additional 1 ns run was performed
using each MD software. This aimed at the elimination of any
eventual problem rising from the fact that the main equilibration
procedure has been made with GROMACS.
The following settings were used in the simulations with the
polarized force field: (i) the atomic polarizabilities previously
reported were selected:34 α(C) = 1.081 Å3, α(H) = 0.389 Å3,
α(O) = 0.354 Å3; (ii) kD = 4184 kJ·mol−1; (iii) mD = 0.4 amu;
(iv) only non-hydrogen atoms were polarized, and the
polarizability of the hydrogens was added to that of the heaviest
element they were attached; (v) except for DL_POLY
calculation, to which 1−4 exclusion was set between induced
dipoles, Thole screening functions were employed with a
damping parameter of a = 2.6 attributed to each atom.
Each production stage consisted of 20 and 10 ns runs for the
nonpolarized and polarized simulations, respectively. A temper-
ature of 298.15 K and a pressure of 1 bar were used by employing
a Nosé−Hoover thermostat and barostat. In the case of the
simulations with GROMACS, as mentioned above, the latter
barostat is not available, so a Parrinello−Rahman was used
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instead. A timestep of 2 fs was selected for the simulations with force field for GROMACS described in this study leads to similar
the nonpolarized force field, while for the polarized runs, a 1 fs results to LAMMPS and CHARMM, which can, in this case, be
was used with GROMACS, CHARMM, and LAMMPS, and 0.5 used as reference data. This suggests that despite the significant
fs with DL_POLY. differences in the model’s implementations, they lead to similar
The simulation results are shown in Table 1. The errors results.
ascribed to the computed values correspond to twice the The data obtained with DL_POLY using the polarizable force
field exhibit the largest deviations to experiment. A close
Table 1. MD Simulation Results for Ethanol at 298.15 K, inspection of the simulation results revealed several issues that
Obtained with DL_POLY, CHARMM, GROMACS, and are worth mentioning. As referred to in Section 3, the use of the
LAMMPS, Using Polarized and Nonpolarized Versions of the Drude/Shell model implies the employment of two thermostats:
OPLS-AA Force Field. The Numbers in Parenthesis one for the Drude particles (set to T = 1 K) and the other for the
Represent the Error Relative to the Experimental Valuesa atom Cores (in this case, 298.15 K). However, as shown in
Figure 3, a constant drift in the Shell particle temperature is
DL_POLY CHARMM GROMACS LAMMPS
nonpolarized
ρ/g cm−3 0.793 ± 0.012 0.782 ± 0.011 0.792 ± 0.793 ±
(1%) (−0.4%) 0.013 0.013
(0.9%) (1.0%)
D/10−9 m2 1.36 ± 0.04 1.41 ± 0.09 1.22 ± 0.14 1.35 ± 0.16
s−1
Uom, cfg(l)/ −16.13 ± −15.49 ± 0.43 −17.38 ± −16.09 ±
kJ mol−1 0.83 0.92 0.70
polarized
ρ/g cm−3 0.888 ± 0.010 0.835 ± 0.004 0.855 ± 0.855 ±
(13.1%) (6.4%) 0.006 0.006
(8.9%) (8.9%)
D/10−9 m2 0.038 ± 0.007 0.426 ± 0.006 0.168 ± 0.243 ±
s−1 0.013 0.043
Uom, cfg(l)/ −36.93 ± 1.5 −27.19 ± 0.39 −29.85 ± −30.26 ±
kJ mol−1 0.85 0.69
a
Experimental reference values at 298.15 K: ρ = 0.785 g cm−3, D = 1.0
× 10−9 m2 s−1.41,42

standard deviation errors (95% confidence level). In general, the

data in Table 1 reveal that independent of the program used, the
values obtained for ethanol using the OPLS-AA force field agree
well with the experiment: (i) the densities show absolute
deviations ≤1% and within the errors of the determinations; (ii)
the self-diffusion coefficient, D, computed from the mean
squared displacement of the molecules in the trajectory, 1.2 < D/
10−9 m2 s−1 < 1.4, are in good agreement with the corresponding
experimental result, D = 1.0 × 10−9 m2 s−1.41,42 The observed
differences between the results found with the four programs are
most likely related to differences in the computation algorithms
(particularly in the case of GROMACS, where a different
barostat was used), a topic that is outside the scope of this study.
The inclusion of polarization in the force field of ethanol
during the simulations leads to a systematic deviation of the
results relative to the experiment, independent of the MD
program. In all cases, an increase in density is observed, with
errors ranging from 6 to 13%. One of the largest discrepancies in
the computed results is observed for the self-diffusion coefficient
(0.14 < D/10−9 m2 s−1 < 0.43, excluding the results for
DL_POLY, which are discussed in detail below), which is one
order of magnitude smaller than the experimental value. The
discussion of the underlying reasons for the discrepancies found
between these results and experiment is difficult to assess and is
outside the scope of this study. Still, recent studies have
highlighted the need for correcting the double counting of
induction and dispersion interactions by scaling the LJ
interactions.27,29 The results shown in Table 1 seem to reinforce
this claim.
Despite the significant differences between the experiment
and theory when polarizable force fields are used, it is important
to note that the proposed implementation of the polarizable
1476
Figure 3. Temperature variation of the Shell, TShell, and Core atoms,
TCore, as a function of the simulation time, obtained using DL_POLY.
noticed, which leads to a change in the different energetic terms
during the simulation (e.g., the Coulomb interaction energy
decreased ∼5 kJ mol−1 in a 2 ns period). This suggests energy
transfers between the Drude particles and the atom Cores.
Because the settings of the Shells thermostat in DL_POLY
cannot be controlled by the user, it is impossible to attempt any
tuning of the temperature control of these particles. To confirm
that the problem was not related to an eventual issue in the force
field implementation, a single point energy calculation was made
using LAMMPS and DL_POLY for the same conformation. The
obtained results were essentially the same for each contribution
(e.g., Ubonds, Uangle, and Udihedral), except for the total Coulomb
energy term, to which a difference of 15 kJ mol−1 was found
using the two programs (Ucoul(DL_POLY) = −13,475 kJ mol−1;
Ucoul(LAMMPS) = −13,460 kJ mol−1). This difference, which
corresponds to 0.1% of the total system energy, most likely, is
related to the use of Thole screening only with LAMMPS. Still, it
is also difficult to relate this fact to a problem in the thermostat.
During this work, this issue was discussed with the DL_POLY
developers. However, until this moment, it was not possible to
https://doi.org/10.1021/acs.jcim.1c01431
J. Chem. Inf. Model. 2022, 62, 1471−1478
Journal of Chemical Information and Modeling
find a solution to the problem. Thus, the use of polarizable force
fields should be performed with caution using this program and,
in the present case, regarded only as indicative.
5.1. Calculation Times. A key question when performing an
MD simulation study is the knowledge of the computational
performance. Because the DLPGEN can implement the same
force field for different programs in the most equivalent way
possible, it was found interesting to benchmark the different free
versions of the supported MD software. These tests were based
on the simulation where liquid ethanol was used as a starting
point, and the simulation boxes obtained from the results are
shown in Table 1. The same simulation conditions described
above were used, with production runs of 10,000 steps, a cutoff
of 14 Å, and timesteps of 1 and 2 fs for the simulations with and
without polarization, respectively. For the sake of consistency,
because DL_POLY and the free version of CHARMM do not
support graphical processing units (GPUs) and have limitations
to the number of central processing units (CPUs) that may be
used, all simulations were performed using up to 8 CPUs. The
calculations were made in a PC equipped with an AMD RYZEN
9 5900X CPU, using the program versions DL_POLY 4.09.4,
CHARMM 44b1 (free), LAMMPS (10 February 2021), and
GROMACS 2021. The obtained results are given in Figure 4
Figure 4. Simulation times obtained in this work for the simulation of
liquid ethanol, during 10,000 steps, with polarized (OPLS-POL) and
nonpolarized (OPLS-AA) versions of the OPLS force field,18 using the
MD programs supported by DLPGEN.
and reveal that CHARMM and DL_POLY are the slowest of the
test set (mind, however, that this may change if the CHARMM
paid version is used). In turn, GROMACS is 6 to 19 times faster
than the remaining programs, when using the nonpolarizable
force field.
The inclusion of polarization dramatically increases the
computation times. The largest impact is noticed for
GROMACS, which increases ∼13 times. This is, most likely,
related to the need of using the slow iterative SCF method. Still,
its computation time is like that of LAMMPS.
6. CONCLUSIONS
In this work, the program DLPGEN, which produces input files
for the MD programs GROMACS, CHARMM, DL_POLY, and
LAMMPS, is described. In the case of the latter three programs,
polarization is introduced using the classical Drude oscillator
approach. For GROMACS, a new Shell model suitable for the
simulation of molecules containing more than one virtual
particle was described. The comparison of the results obtained
for liquid ethanol using the polarizable models revealed that
both static (configurational energy and liquid densities) and
1477
pubs.acs.org/jcim Article
dynamic properties (self-diffusion coefficient) obtained using
GROMACS are in good agreement with the data obtained with
LAMMPS and CHARMM. This suggests that the proposed
methodology is suitable for the simulation of polarized systems
using GROMACS without a significant increase in the
computational time relative to the remaining programs. In the
case of the simulations performed using DL_POLY, a problem
related to the thermalization of the Shells particles was noticed.
This suggests that the use of this program with molecules
containing multiple Drude particles should be performed with
caution.
■ AUTHOR INFORMATION
Corresponding Author
Carlos E. S. Bernardes − Centro de Química Estrutural,
Institute of Molecular Sciences, Faculdade de Ciências,
Universidade de Lisboa, Lisboa 1749-016, Portugal;
orcid.org/0000-0003-1490-9728; Email: cebernardes@
fc.ul.pt
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jcim.1c01431
Notes
The author declares no competing financial interest.
The program DLPGEN and the documentation necessary to
reproduce the data in the study are freely available for download
at https://bit.ly/3E8nHx2.
■ ACKNOWLEDGMENTS
This work was supported by Fundaçaõ para a Ciência e a
Tecnologia (FCT), Portugal (projects PTDC/QUI-OUT/
28401/2017, LISBOA-01-0145-FEDER-028401, LA/P/0056/
2020, UIDB/00100/2020, and UIDP/00100/2020). The
author would also like to acknowledge Prof. José N. Canongia
Lopes (Univ. Lisbon), Prof. Agílio A. H. Pádua (ENS de Lyon),
and Prof. Christian Schröder (Univ. Vienna) for the useful
discussions.
■
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