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Rational Design of Methodology-Independent Metal Parameters

Using a Nonbonded Dummy Model
Yang Jiang,† Haiyang Zhang,‡ and Tianwei Tan*,†
†
Beijing Key Lab of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029,
China
‡
Department of Biological Science and Engineering, School of Chemistry and Biological Engineering, University of Science and
Technology Beijing, 100083 Beijing, China
*
S Supporting Information

ABSTRACT: A nonbonded dummy model for metal ions is

highly imperative for the computation of complex biological
systems with for instance multiple metal centers. Here we
present nonbonded dummy parameters of 11 divalent metallic
cations, namely, Mg2+, V2+, Cr2+, Mn2+, Fe2+, Co2+, Ni2+, Zn2+,
Cd2+, Sn2+, and Hg2+, that are optimized to be compatible with
three widely used water models (TIP3P, SPC/E, and TIP4P-EW).
The three sets of metal parameters reproduce simultaneously the
solvation free energies (ΔGsol), the ion−oxygen distance in the
first solvation shell (IOD), and coordination numbers (CN) in
explicit water with a relative error less than 1%. The main sources
of errors to ΔGsol that arise from the boundary conditions and
treatment of electrostatic interactions are corrected rationally,
which ensures the independence of the proposed parameters
on the methodology used in the calculation. This work will be of great value for the computational study of metal-containing
biological systems.

1. INTRODUCTION coordination geometry simultaneously by introducing a

Metal ions in the biomolecular system have multiple functions
and play an important role in the catalytic process.1 For
computational studies of metalloenzymes, one of the most
challenging tasks is to develop suitable force field para-
meters for metal ions, especially for divalent metal ions.
Three strategies for metal modeling have been proposed: the
bonded,2 nonbonded point charge,3,4 and nonbonded dummy
atom models.5−9 The bonded model has predefined covalent
bonds or harmonic restrains between the metal and ligands and
can reproduce a highly accurate crystal structure. The force field
parameters of the metal−ligand complex are usually generated
and optimized by quantum mechanics (QM) calculations.2
However, once the ligand is altered, the bonded model pa-
rameters need be reoptimized to match the new metal site.
Moreover, it does not allow ligand exchange during the
simulation. The point charge model is simply described as a
point charge surrounded by van der Waals (vdW) potentials.
Only the parameters of vdW potentials need to be optimized.3,4,10
Although the point charge model allows ligand exchange, it will
be inadequate when the simulation system has a complex metal
center (two or more metal ions in one active site) or transition
metals are present.6,11 Recently, Li and Merz have presented the
Particle Mesh Ewald (PME)12 compatible point charge model
parameters for 16 divalent metal ions, and these parameters
reproduce the experimental solvation free energy and the
12−6−4 Lennard-Jones (LJ) potential.4 However, the coordi-
nation numbers (CNs) of V2+, Mn2+, Cd2+, Sn2+, and Hg2+ were
not modeled accurately. The nonbonded dummy atom model
makes a good balance between the former two models. It
was originally presented by Åqvist and Warshel,11 and then
improved by many researchers.5−9,13 This model was originally
designed for the divalent metal ions with CN equal to six.
The metal ion has a metal core (MC) surrounded by six dummy
atoms (D) to form an octahedron (Figure 1). There are
covalent bonds (b0) between MC and the dummy atoms, but
no covalent bond between the dummy atom and the ligand,
which hence allows ligand exchange. Recently, Duarte et al.8
Figure 1. Geometry of the nonbonded dummy atom model. The
metal center (MC) with a charge of n-6δ bond covalently to six
dummy atoms (D) with a charge of + δ to form an octahedron.
Received: February 29, 2016
Published: May 16, 2016

© 2016 American Chemical Society 3250 DOI: 10.1021/acs.jctc.6b00223

J. Chem. Theory Comput. 2016, 12, 3250−3260
Journal of Chemical Theory and Computation
have optimized dummy model parameters of seven divalent
metal ions, including Mg2+, Mn2+, Fe2+, Co2+, Ni2+, Zn2+, Ca2+,
using the OPLS-AA force field, and Liao et al.9 have provided
the dummy atom model of Cu2+ that includes the Jahn−Teller
effect.
Till now, all the proposed dummy atom models, even most
of the nonbonded models, were optimized to reproduce the
experimental solvation free energies (ΔGsol) provided by
Noyes,14 Rosseinsky,15 or Marcus.16 These three sets of ΔGsol
were derived from the so-called “conventional” values calculated
using the tabulated thermodynamics data from National Bureau
of Standards (NBS), followed by adding the proton hydration
free energy and then converted to the “absolute” values. The
proton hydration free energy cannot be directly measured by
experiments, so different methods were used to obtain this value.
Marcus derived the proton hydration free energy based on the
extra-thermodynamic assumption “TATB hypothesis”,17 which
is different from the methods reported by Rosseinsky15 and
Noyes,14 leading to deviations between the three sets of ΔGsol.
Later on, another proton hydration free energy was provided by
Tissandier et al.18 using the cluster pair approximation method,
which was considered to be accurate and recommended by
several reports.19−21 However, no revised experimental solvation
free energies for the divalent metal ions based on Tissandier’s
proton hydration free energy have been reported and used as the
reference for force field development, except for our previous
work13 in which we demonstrated a remarkable advantage of
using the revised experimental solvation free energy for the Mg2+
dummy model in refining the parameter. In the present work,
the experimental solvation free energies of the divalent metal
ions taken from Marcus16 are revised using Tissandier’s proton
hydration free energy (details were shown in Supporting
Information, Table S1). Considering that Cu2+ has the Jahn−
Teller effect and has been optimized well before,9 we take
the remaining 11 ions, namely, Mg2+, V2+, Cr2+, Mn2+, Fe2+,
Co2+, Ni2+, Zn2+, Cd2+, Sn2+, and Hg2+, to develop the dummy
atom models for TIP3P, SPC/E, and TIP4P-EW water models,
respectively.
In addition, a free energy correction is introduced into the
parameter generation procedure, including the correction for
use of periodic boundary conditions with the PME method
and the correction for an improper summation scheme.22
More details on the free energy corrections are presented in
section 2.5. Considering these corrections makes the calculated
free energy independent of the simulation methodology such as
the finite system, the lattice-sum, and the cutoff-based methods.22
That is, the optimized models in this work can reproduce the
experimental solvation free energies using any of the above three
simulation methodologies just by adding the corresponding
corrections.22 The major strength of our models is that they can
reproduce accurate coordination geometries without high-level
QM calculations and without additional modifications of the van
der Waals (vdW) potential such as the 12−6−4 LJ potential
proposed by Li and Merz,4 especially for V2+, Cd2+, Sn2+, and
Hg2+, whose CN values cannot be reproduced correctly by a
nonbonded model. Unlike the point charge metal parameters
presented by Li and Merz that are only compatible with the PME
simulations, the models in this work are in principle compatible
with almost all the simulation systems.
2. MATERIALS AND METHODS
2.1. Force Field Used in This Work. To generate the
dummy atom model parameters of the 11 divalent metal ions,
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we used Duarte’s parameters as the reference.8 The values of
force constants (Kb for bonds and Kθ for angles), equilibrium
bond length (b0) and angle (θ0), atomic mass and charge of
Duarte’s model were still used here. The vdW parameters
for each metal type were set to be the vdW radius (R) and the
12−6 LJ potential well depth (ε). The nonbonding interaction
potential function of two atoms i and j in the AMBER ff03 force
field used in the present study has the following form:23
Uijnonbond(rij) = UijvdW(rij) + Uijele(rij)
⎡⎛ ⎞12 ⎛ R ij ⎞6 ⎤ qiqj
R ij
= εij⎢⎜⎜ ⎟⎟ − 2⎜⎜ ⎟⎟ ⎥⎥ + k
⎢
⎣⎝ ij ⎠ ⎝ rij ⎠ ⎦
r rij
(1)
where rij is the distance between atom i and j in Å, qi is the
charge of atom i in e, and k is a constant equaling 332. Rij and εij
satisfy the Lorentz/Berthelot mixing rules:
⎧ 1
⎪ R ij = (R ii + R jj) = R i + R j
⎨ 2
⎪ε = ε ε = ε ε
⎩ ij ii jj i j (2)
Note that Ri here is the same as Rmin/2 in many other papers.
2.2. Experimental Values Used in This Work. The
experimental values of the ion-oxygen distance (IOD) and
the coordination number (CN) for each metal were obtained
from several works24−27 (shown in Table S1). The experimental
value of the solvation free energy ΔGexp sol was obtained from
Marcus’s work16 and then revised by the accurate value of
the proton hydration free energy recommended by many
reports.18−21 The proton hydration energy (−265.9 kcal/mol)
has been corrected by converting the 1-atm gas phase standard
state ΔG sol
o
to the 1 M solution standard state ΔG sol *
(by subtracting ΔGo→* = 1.9 kcal/mol).19 Note that, Marcus’s
solvation free energies also have been corrected to the 1 M
solution standard state, but the correction seems to have the
wrong direction in his work16 (ΔGo→* was added to ΔGosol).
Thus, for the absolute solvation free energy provided by Marcus
* ), the conventional ionic solvation free energy ΔGconv
(ΔGMarcus sol
can be derived by
conv
ΔGsol *
= ΔGMarcus − ΔGo →* − zΔG H (3)
where ΔG*Marcus is under 1 M solution standard state, z is the net
charge of the ion (2 for divalent ions), and ΔGH is the proton
hydration free energy (−252.3 kcal/mol from Marcus). Then
our revised metal ionic solvation free energy can be derived
by using the accurate proton hydration free energy (ΔGH =
−265.9 kcal/mol) and then corrected to the 1 M solution
standard state:
exp
ΔGsol conv
= ΔGsol + zΔG H − ΔGo →* (4)
The revised experimental solvation free energies for the divalent
metal ions are shown in Table S1.
2.3. General Approach of Molecular Simulations. All
simulations were performed using the AMBER14 suite28 with
the all-atom ff03 force field.29 A 1000 step energy minimization
was performed to eliminate improper contacts in each system.
After energy minimization, each system was heated gradually
from 0 to 298 K. During the heating steps, position restraints
were imposed on the metal ions with a force constant of
10.0 kcal/mol/Å2. Each system was then equilibrated at the
constant temperature (298 K) and pressure (1 bar) conditions
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via the Langevin dynamics (the collision frequency is 1.0 ps−1),
with a coupling constant of 0.2 ps for both parameters. All
the production simulations were performed at 298 K and 1 bar
using a time step of 2 fs. Electrostatic interactions were
calculated using the PME algorithm. The cutoff distance for van
der Waals interactions was 10.0 Å. The SHAKE algorithm30
was applied to the bonds involving hydrogen.
2.4. Two-Step Thermodynamic Integration. The
solvation free energy ΔGsol of metal ion M2+ was calculated
using the two-step thermodynamic integration (TI) method.
The first step was perturbing nothing to the metal atom M
(with no charge) in water using the soft-core potential
(“appearing” part) in Amber11 suite.31 For the parameter
dVSC
generation, dλ
was calculated from five independent
simulations at λ = 0.04691, 0.23076, 0.50000, 0.76923, and
0.95308, including a 400 ps energy equilibration and a 100 ps
dV
production. For the model testing, dλSC was calculated from
nine independent simulations at λ = 0.01592, 0.08198, 0.19331,
0.33787, 0.50000, 0.66213, 0.80669, 0.91802, and 0.98408. The
dV
parameters of soft-core potential were set to default. dλSC was
obtained from the production simulation. The free energy
change ΔGvdW SC
was then calculated using the Gaussian
dV
quadrature formulas. The dλSC plots for the metal ions cal-
culated using the final parameters for TIP3P water were shown
in Figure S1. Others are similar to these and not shown.
The second step was charging the metal M from 0 e to +2 e
dU
by a parameter λ. For the parameter generation, dλ was
calculated from five independent simulations at λ = 0.04691,
0.23076, 0.50000, 0.76923, and 0.95308, including a 400 ps
energy equilibration and a 100 ps production. For the model
dU
testing, dλ was calculated from nine independent simulations
at λ = 0.01592, 0.08198, 0.19331, 0.33787, 0.50000, 0.66213,
dU
0.80669, 0.91802, and 0.98408. dλ was obtained from the
production simulation. The free energy change ΔGMTI0→M2+
was then calculated using the Gaussian quadrature formulas.
dU
The dλ plots for the metal ions calculated using the final
parameters for TIP3P water were shown in Figure S1. Others
are similar to these and are not shown.
2.5. Free Energy Correction. The correction for the raw
ionic charging free energies has been discussed and provided
by many reports.21,22,32−34 Two different correction terms
should be added to the calculated solvation free energy.
The first term ΔGPBC corr is the correction for using the periodic
boundary condition (PBC) with the PME approach. PME is
one of the most popular lattice-sum (LS) methods. For the
PME approach, the ion−ion self-potential is already included in
the instantaneous electrostatic potential of the ion.33 This is dif-
ferent from the general LS method. So the ion−ion self-potential
term should be eliminated from the general finite-size correction.
Thus, the correction for using PBC with the PME approach is
given by
PBC q2 ξLS
ΔGcorr =−
8πε0εs L
q2 1 − εs−1 ⎡ 4π ⎛ RI ⎞2 16π 2 ⎛ RI ⎞5⎤
+ ⎢ ⎜ ⎟ − ⎜ ⎟ ⎥
8πε0 L ⎣ 3 ⎝L⎠ 45 ⎝ L ⎠ ⎦ (5)
where q is the ionic charge (+2 e); εs is the solvent permittivity
(78.0 for water); L is the box boundary length estimated from the
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equilibration simulation; RI is the ionic radius, which is defined
to be the distance value where the ion-oxygen radial distribution
function (RDF) begins to accumulate;34 ξLS is a constant and
approximately equals to −2.837297.22,33,34
The second term ΔGϕcorr is the correction mainly for the
error in the potential at the ionic site due to its evaluation
using an improper summation scheme.22,35 In this study, we
used the formula provided by Kastenholz et al.22 to estimate
this term:
⎛ 4πRI 3 ⎞ ργ 4πRI 3
ϕ
ΔGcorr = −q⎜1 − ⎟ − q (16.8 − 26/RI)
⎝ 3L3 ⎠ 6ε0 3L3
(6)
−3
where ρ is the solvent number density (0.033 Å for all the TI
simulation systems); γ is the quadrupole-moment trace of the
solvent molecule:22
Ns
γ= ∑ qiri 2
i (7)
where qi is the partial charge of atom i in the solvent molecule;
ri is the distance between the M site and atom i of the solvent
molecule; Ns is the total atom number of the solvent molecule.
The quadrupole-moment traces for the three different water
models used in this work were shown in Table S2. Note that
the last term of ΔGϕcorr corrects the error due to the possible
presence of a constraint of vanishing average potential over
the computational box and depends on the potential jump at
the ion−solvent interface (for the PBC system with the LS
scheme).22,35,36 It has a negligible magnitude because of RI ≪ L
in the present case. We still retain this negligible term here to
keep consistent with the previous work.13
The correction technology for the charging free energy of the
multiatomic system has been proposed by Reif et al.21 and
Rocklin et al.,37 which can only be estimated through numerical
methods. Because of the small volume with symmetrical charge
distribution of the dummy model, the shift in ΔGPBC corr due to the
different charge distribution of our dummy model compared
with the point charge model can be ignored. Moreover, because
of the eliminated self-potential, ΔGPBCcorr is less than 2 kcal/mol
with the ionic radius less than 2.5 Å, leading the small effect of
the ΔGPBC corr . Therefore, although the dummy model contains
more than one charged atom, the above correction technology
for the monatomic ion, as a fast estimation, is still adapted to
our dummy model.
Note that there is no need to add the correction for the
truncated vdW interaction, because Amber has already added
this correction into its calculation protocol (see the keyword
“vdwmeth” in Amber’s manual, http://ambermd.org/doc12/
Amber14.pdf). Note that there is also no need to add the
correction for standard state ΔGo→* here, because our revised
experimental solvation free energy has been already corrected
into the 1 M solution standard state. Therefore, the solvation
free energy was finally calculated by
cal
ΔGsol SC
= ΔGvdW TI
+ ΔG M PBC
+ ΔGcorr ϕ
+ ΔGcorr
0
→ M2 + (8)
2.6. Parameters Generation Process. The vdW param-
eters R and ε for each divalent metal ion and each water
model were generated by following the process similar to that
provided by Li et al.3 The parameter space was defined to be
R ∈ [0.30 Å, 1.50 Å] and ε ∈ [10−3 kcal/mol, 200 kcal/mol],
and then divided into forty-two discrete points, which were
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the combinations of R = 0.30, 0.50, 0.75, 1.00, 1.25, 1.50 Å and
ε = 10−3, 10−2, 10−1, 1, 10, 100, 200 kcal/mol. At each point,
the dummy atom model was built with the specific vdW
parameter combinations. The mass of the metal center of each
dummy atom model was set to be 6.3 (the choice of mass has
a limited influence on the simulated solvation free energy and
the coordination geometry of the metal ion−water system3).
The dummy atom model at each point was then solvated in
three cubic boxes with a total of 1075 water molecules (the
box length L is 31.65 Å) parametrized by TIP3P, SPC/E, and
TIP4P-EW model, respectively.
The solvation free energy ΔGcalsol for each system was cal-
culated using the accurate “two-step” thermodynamic integra-
tion (TI) and then added by the free energy corrections. The
CN value was defined to be the integral value (N[g(r)]) of the
metal−oxygen radial distribution function (g(r)) from 0 Å to
the distance value (dm) at the minimum between the two peaks
of the RDF:
CNRDF = ∑ Δn(rj)
0 ≤ r j ≤ dm (9)
where rj is the MC-O distance for the RDF; Δn(rj) is the
unnormalized oxygen atom number on the sphere surface
with rj as the radius. The RDF was calculated using the
trajectory produced by a 1 ns production MD simulation with
the interval 0.01 Å. The IOD value for each system was
derived by fitting the first pick of RDF using the quadratic
function and described in detail by Li et al.3 The IOD value
was then defined to be the distance at the first peak of the
RDF and named IODRDF. All the scanned data are shown in
Tables S3−S5.
After the three quantities for all the discrete points within the
parameter space were calculated, the surface of the ΔGsol and
the IODRDF can be reproduced by using the 2D cubic spline
interpolation in MATLAB.38 For each metal ion, the contour
curves which represent the values equaling the experimental
ΔGsol value and the experimental IOD value can be both found
and then plotted on one graph with −lg(ε) as the horizontal
axis and R as the vertical axis. The intersection point of these
two contour curves was then searched within the parameter
space by finding the zero point for the difference function
of the two contour curves fitted using the 1D cubic spline inter-
polation in MATLAB. The intersection was the target parameter
Figure 2. ΔGsol (a) and IOD (b) surfaces for the parameter generation with TIP3P water model. The parameter space is shown as the x−y plane
with R ∈ [0.3000, 1.5000] and −lg(ε) ∈ [−2.3010, 3.0000].
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combination that can both reproduce the experimental solvation
free energy and the coordination geometry.
2.7. Model Testing. For each of the parameters generated
from the previous section, the relative errors of the reproduced
ΔGsol and IOD values related to the respective experimental
values were calculated after longer and more careful MD and TI
simulations than those in the parameter generation process. For
MD simulations, 1000-step energy minimization, 60 ps heating,
500 ps equilibration, and 10 ns production were performed. For TI
simulations, more λ values were used as described in section 2.4.
IODRDF were calculated using the 10 ns production trajectories.
To test other relevant properties that were not directly
parametrized, we calculated the water exchange rate of the
present Mg2+ model and compared it with those provided by
Allnér,39 Duarte,8 and Li and Merz.4 The Li and Merz 12−6−4
potential parameters were generated using AmberTools15,40
in which the bug in calculating the 12−6−4 parameter in
AmberTools14 has been fixed. To calculate the water exchange
rate, we followed the procedure described by Allnér et al.39 The
brief calculation scheme is as follows: The potential of mean
force (PMF) was calculated along the reaction coordinate,
which is the distance (x) between the metal ion and the water
oxygen atom from 1.6 to10.0 Å, using the umbrella sampling.
The interval between 1.6 and 6 Å was 0.1 Å with a force
constant of 150 kcal/(mol·Å2), and the interval between 6 and
10 Å was 0.5 Å with a force constant of 10 kcal/(mol·Å2),
leading to a total of 53 simulation windows. For each window,
the simulation included 1000-step energy minimization with a
force constant of 500 kcal/(mol·Å2), 100 ps equilibration, and
1 ns production. The PMF curves were then generated using the
weighted histogram analysis method41 with a tolerance of 10−5. An
entropic contribution, S = 2 RT ln(x), to the average constraint
force due to the free rotation of the solute−solute connecting
vector was subtracted out from the PMF values.39 The rate
constant k was then calculated according the following equation:39
†
k = Ae−ΔG / RT (10)
†
where ΔG is the free energy of activation estimated from the
PMFs as the energy difference between the global minimum and
the global maximum, R is the ideal gas constant, and T is the
temperature. A is the pre-exponential factor and calculated by
1 E″
A=
2π μ (11)
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where E″ is the second derivative of the PMF calculated by
fitting a quadratic function to the bottom data points, and μ is
the reduced mass of the atom pair.39
To demonstrate the simulation performance of our para-
meters in an actual biomolecule system, we followed the study
Figure 3. Intersection points of contour curves for the parameter
generation with TIP3P water model. The parameter space is shown as
the x−y plane within R ∈ [0.3000, 1.5000] and −lg(ε) ∈ [−2.3010,
3.0000]. The contour curves of ΔGsol and IODRDF are shown by solid
and dotted lines, respectively. ΔGsol contour curves of Hg2+ and Mn2+
are overlapped because of the same free energy values, and thus only
the curve for Mn2+ is given here.
of Duarte et al.8 We chose the E. coli Glyoxalase I (GlxI,
PDBID: 1F9Z42) to perform our testing. The origin metal ion
was Ni2+ and we then replaced it with Co2+, Cd2+, and Zn2+.
The ion parameters of Li-Merz 12−6−44 were also tested.
The MD simulation setup can be found in section 2.3, and the
12−6−4 parameters were generated using AmberTools15.40
Note that, in this study, we did not modify the partial charge
on the coordinated oxygen atoms of Glu56 and Glu122. Each
simulation included a 5000-step energy minimization, 60 ps
heating, 500 ps equilibration, and 20 ns production.
2.8. Coordination Number Optimization. For the
models that failed to reproduce the experimental CN values,
we reoptimized the MC-D bond length (b0) and the partial
charge on D (δ). First, the b0-δ parameter space was scanned at
b0 = 0.8, 0.9, 1.0, 1.1, 1.2, and 1.3 Å, and δ = 0.3, 0.4, 0.5, 0.6,
and 0.7 e, with several fixed R and ε values in the TIP3P water.
We found that increasing the b0 and δ values can increase the
IOD threshold that determines the CN value to be six or not.
Hence, the b0-δ combinations that show the IOD threshold
exceeding the target experimental IOD values were selected.
They are b0 = 1.1 Å and δ = 0.7 e for Cd2+, b0 = 1.3 Å and
δ = 0.7 e for Sn2+, and b0 = 1.2 Å and δ = 0.6 e for Hg2+. Second,
the same parameter generation procedure was applied on these
three b0-δ combinations with TIP3P, SPC/E, and TIP4P-EW
water models. For Cd2+, the R-ε space was defined to be
R ∈ [0.75 Å, 1.50 Å] and ε ∈ [0.1 kcal/mol, 100 kcal/mol].

Table 1. Reproduced Coordination Geometries and Solvation-Free Energiesa of Models for the 11 Divalent Metal Ions Selected
from the Parameter Generation Process for TIP3P Water (Parameters with Bad Performances Were Marked in Bold)
revised ΔGexp
sol IODexp IODRDF RI ΔGTI
M0→M2+ ΔGSC
vdW ΔGcorr ΔGcal
sol

metal ions kcal/mol Å CN Å CNRDF Å kcal/mol

Mg2+ −468.2 2.090 6 2.088 6.0 1.93 −433.68 0.70 −33.96 −466.9
V2+ −467.0 2.210 6 2.189 6.0 2.08 −412.53 −23.06 −33.90 −469.5
Cr2+ −473.0 2.080 6 2.079 6.0 1.94 −437.69 0.49 −33.95 −471.2
Mn2+ −451.5 2.192 6 2.186 6.0 2.07 −408.84 −10.91 −33.90 −453.6
Fe2+ −470.6 2.114 6 2.113 6.0 1.99 −431.23 −5.01 −33.93 −470.2
Co2+ −488.5 2.106 6 2.103 6.0 1.96 −440.35 −15.28 −33.94 −489.6
Ni2+ −504.1 2.061 6 2.065 6.0 1.93 −452.48 −14.98 −33.96 −501.4
Zn2+ −498.1 2.098 6 2.096 6.0 1.98 −444.77 −19.05 −33.94 −497.8
Cd2+ −450.3 2.301 6 2.279 6.6 2.12 −394.25 −22.77 −33.88 −450.9
Sn2+ −387.0 2.620 6 2.594 8.6 2.39 −338.27 −16.38 −33.77 −388.4
Hg2+ −451.5 2.410 6 2.388 7.9 2.21 −382.48 −36.02 −33.85 −452.4
a
The detail values of free energy calculation and correction are shown in the table. RI is the ionic radius that is derived from the RDF plot and used
ϕ
to calculate the free energy correction. ΔGcorr is the sum of ΔGPBCcorr and ΔGcorr calculated using eq 5 and 6.

Table 2. Reproduced Coordination Geometries and Solvation Free Energiesa of the CN-Optimized Models for Cd2+, Sn2+,
and Hg2+
revised ΔGexp
sol IODexp IODRDF RI ΔGTI
M0→M2+ ΔGSC
vdW ΔGcorr ΔGcal
sol

metal ions kcal/mol Å water model Å CNRDF Å kcal/mol

Cd2+ −450.3 2.301 TIP3P 2.301 6.0 2.16 −412.57 −4.42 −33.35 −450.3
SPC/E 2.300 6.0 2.16 −412.44 0.45 −37.17 −449.2
TIP4P-EW 2.301 6.0 2.18 −401.27 −7.81 −41.61 −450.7
Sn2+ −387.0 2.620 TIP3P 2.623 6.0 2.50 −340.02 −13.96 −33.09 −387.1
SPC/E 2.611 6.0 2.47 −343.46 −7.27 −36.93 −387.7
TIP4P-EW 2.610 6.0 2.47 −333.33 −12.46 −41.38 −387.2
Hg2+ −451.5 2.410 TIP3P 2.411 6.0 2.29 −399.99 −18.84 −33.26 −452.1
SPC/E 2.410 6.0 2.27 −402.18 −13.69 −37.09 −453.0
TIP4P-EW 2.415 6.0 2.30 −384.75 −26.95 −41.52 −453.2

a
The detail values of free energy calculation and correction are shown in the table. RI is the ionic radius that is derived from the RDF plot and used
ϕ
to calculate the free energy correction. ΔGcorr is the sum of ΔGPBCcorr and ΔGcorr calculated using eq 5 and 6.

3254 DOI: 10.1021/acs.jctc.6b00223

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Journal of Chemical Theory and Computation Article

For Sn2+, the R-ε space was defined to be R ∈ [1.25 Å, 1.75 Å]

and ε ∈ [0.1 kcal/mol, 100 kcal/mol]. For Hg2+, the R-ε space
was defined to be R ∈ [0.75 Å, 1.50 Å] and ε ∈ [0.1 kcal/mol,
200 kcal/mol]. Note that the water box here was smaller than
that in the original procedure in section 2.6 and contained
580 water molecules (the box length L is 26.03 Å) in order to
speed up the parameter generation procedure. Finally, all
the parameters for each water model and each metal ion were
optimized and tested to check the simulation performance.
2.9. Model Refining. For the bad models, whose relative
errors of the reproduced ΔGsol and IOD values exceed 1%,
a parameter refining process should be performed on them.
The parameter refining process was described in detail in our
previous work.13 The process starts from defining an initial
hunting zone according to the initial parameter combination.
Through step 1, parameters that can produce IOD values all
close to the experimental IOD value after energy minimizations
are retained. Through step 2, parameters that can the produce
IODRDF value close to the experimental IOD value after 10 ns
MD simulations are retained. Through step 3, parameters
that can produce a solvation free energy close to the revised
experimental value can be retained. The parameter combination
with the closest calculation values to the experimental values is
finally selected to terminate the process; otherwise a narrower
hunting zone according to the eligible parameter combinations
produced by step 2 is defined and a new iteration starts. Here,
we used these bad model parameters as the initial values to start
the process. The threshold values for step 1 and 2 were set
to be 0.01 Å for the first iteration. Fortunately, the refining
processes found the optimal parameters after one step iteration.

3. RESULTS
3.1. Parameter Development. For the development
procedure of the force field parameters, the vdW parameter
Rmin/2 (written as R for convenience hereinafter) and ε for
each model need to be optimized; the other parameters were
taken from our previous work13 (note that the MC-D bond
length b0 was 0.9 Å and the partial charge δ was 0.5 e). The
solvation free energies (ΔGsol), ion-oxygen distances in the first
hydration shell (IOD), and CN values for the parameter
combinations at the discrete points within the parameter space
were calculated. The ΔGsol surface and the IOD surface for
each water model were both generated, and the two surfaces for
the TIP3P water model were shown in Figure 2; the surfaces
for SPC/E and TIP4P-EW water models are given in Figure S2
and Figure S3, respectively. The ΔGsol surface for the TIP4P-
EW model showed slightly higher values than those for the
TIP3P and SPC/E models. All the IOD surfaces display similar
landscapes. Contour curves that represent the experimental
values of the ΔGsol and the IOD values of the 11 divalent metal
ions were then plotted on the parameter space, and the one for
TIP3P water was shown in Figure 3; the curves for SPC/E
and TIP4P-EW water models are given in Figure S4. The
intersection points of the ΔGsol and the IOD contour curves
were clearly marked and then transformed to the parameters of
the 11 divalent metal ions.
The generated parameters were then tested to produce the
ΔGsol, IOD and CN values by more careful calculations
described in Section 2.7. The above values are shown in Table 1
for TIP3P water, Table S6 for SPC/E water, and Table S7
for TIP4P-EW water. For the current parameters, the CN
values of Cd2+, Sn2+, and Hg2+ were all produced incorrectly,
indicating somewhat a failure of reproducing CN values for the
3255
Figure 4. Relative errors of the calculated values of IODRDF (red) and
solvation free energy (blue) for the 11 divalent metal ions simulated
using the parameters for (a) TIP3P water, (b) SPC/E water, and
(c) TIP4P-EW water models before being refined. The experimental
values of IOD and solvation free energy of the 11 divalent metal ions
(can be found in Table 1) are used as the standard. The threshold
value 1% is represented by a dotted line in each plot. For TIP4P-EW,
the relative errors of IODRDF for V2+ and Ni2+ exceed the threshold,
leading us to perform a parameter refining process for these two metal
ions with TIP4P-EW water.
six-coordinated divalent metal ions with the IOD values
exceeding 2.30 Å. The CN values for the metal ions with
IOD lower than 2.30 Å were all reproduced accurately. Now,
the IOD threshold that determines the CN value to be six was
2.30 Å. The b0-δ space with several fixed R and ε values were
then scanned to find appropriate b0-δ combinations that can
keep CN being six for Cd2+, Sn2+, and Hg2+. It was found
that increasing b0 and δ values can increase the above IOD
threshold. Finally, three different b0-δ combinations were found:
b0 = 1.1 Å and δ = 0.7 e for Cd2+, b0 = 1.3 Å and δ = 0.7 e
for Sn2+, and b0 = 1.2 Å and δ = 0.7e for Hg2+. For each
DOI: 10.1021/acs.jctc.6b00223
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Table 3. Final Optimized Force Field Parameters of the 11 Divalent Metal Ions for TIP3P, SPC/E, and TIP4P-EW Water
Models
Force Field Parametersa
b0
bond typeb Kb Cd Sn Hg others
MCDi 800.0 1.1 1.3 1.2 0.9
angle typec Kθ θ0
DiMCDi 125.0 180.0
DiMCDj≠i 125.0 90.0
Mass, Charge and Nonbonding Parametersd
TIP3P SPC/E TIP4P-EW
atom type mass charge R ε R ε R ε
MC Mg 6.31 −1.00 0.9203 0.2394 1.2392 0.0096 0.6036 5.6131
V 32.94 −1.00 0.6775 93.2484 0.7010 88.2098 0.6360 144.5440
Cr 34.00 −1.00 0.8480 0.3014 1.1758 0.0116 0.5274 9.9596
Mn 36.94 −1.00 0.7646 25.6237 0.8147 14.5482 0.6966 43.1992
Fe 37.85 −1.00 0.6857 9.6775 0.8254 1.2306 0.5568 24.5709
Co 40.93 −1.00 0.5348 64.8829 0.5651 34.4805 0.4734 107.8194
Ni 40.69 −1.00 0.4152 83.3241 0.3997 34.5862 0.3280 201.3724
Zn 47.39 −1.00 0.4895 100.7481 0.5004 57.3981 0.4523 187.4485
Cd 94.40 −2.20 1.0228 4.9444 1.2711 0.3978 0.8844 11.6724
Sn 100.70 −2.20 1.4313 12.9508 1.5131 5.3147 1.3786 12.2698
Hg 182.60 −2.20 0.9903 41.4921 1.0285 22.9838 0.9106 74.5833
atom type mass charge R ε
Di Cd 3.00 0.70 1.3882 1 × 10−8
Sn 3.00 0.70
Hg 3.00 0.70
Others 3.00 0.50
a
The atom types of the metal core and the dummy atom is MC and Di. The dummy atoms have three types and named D1, D2, and D3. bUb = Kb(b − b0)2,
where Kb is in kcal·mol−1 Å−2 and b0 is in Å. cUθ = Kθ(θ − θ0)2, where Kθ is in kcal·mol−1 rad−2 and θ0 is in degrees. dThe nonbonding parameters
R and ε follow the Lorentz/Berthelot combination rule. The unit of R, i.e. Rmin/2 in many other papers, is Å. The unit of ε is kcal/mol.

combination, the R and ε values were reoptimized for TIP3P,
SPC/E, and TIP4P-EW water models through the same
parameter generation procedure described above. All the
new scanned models for Cd2+, Sn2+, and Hg2+ can correctly
reproduce the experimental values of CN, as well as the ΔGsol
and the IOD values (see Table 2).
After CN optimization, for the two parameter sets of TIP3P
and SPC/E, the relative errors for ΔGsol and IOD are all less
than 1% (Figure 4a and Figure 4b), indicating a remarkable
accuracy of ΔGsol and IOD surfaces from the parameter genera-
tion process. However, for the TIP4P-EW water, the relative
errors of IOD for V2+ and Ni2+ exceed 1% (Figure 4c),
indicating that some deviations exist on the surfaces around the
points of V2+ and Ni2+. We further performed the parameter
refining process proposed in our previous work13 for V2+ and
Ni2+ with TIP4P-EW water to find the optimal parameter
combinations. The parameter combinations for V2+ and Ni2+
produced by the parameter generation process for TIP4P-EW
water were already close to the optimal points and were
therefore used as initial values of the parameter refining process.
After only one round of iteration, the optimal parameter
combinations were found. The details were given in Table S8.
At this time, all the parameters of the 11 divalent metal ions for
the three water models were completely developed (given in
Table 3). They can accurately reproduce the experimental ΔGsol
and IOD values with relative errors less than 1%. All these
models can reproduce the experimental CN values to be six.
3.2. Parameter Testing. In our previous work,13 the
advantage and drawback of the dummy atom model have been
3256
discussed in detail. Here, we performed simple tests for the
present dummy atom models to show their simulation
performance of reproducing the water exchange rate constant
and the geometry of a metal center in a biological system.
The water exchange rate constants of Mg2+ calculated using
the present dummy model, the Duarte dummy model, the
Allnér model, and the Li and Merz 12−6−4 model were shown
in Table 5. The calculated water exchange rate constants were
compared with the experimental value (6.7 × 105 s−1) provided
by Bleuzen et al.43 The comparison indicates that the dummy
atom models (the present model and the Duarte model) could
estimate a higher energy barrier (ΔG†), leading to a lower
water exchange rate constant. On the contrary, the Li and Merz
12−6−4 models could estimate a lower energy barrier (ΔG†),
leading to a higher water exchange rate constant. The Allnér
model, which is exactly optimized for reproducing the water
exchange rate, produced the best result (6.87 × 105 s−1).
Among the remainder of the models, the Duarte model for
TIP3P water (3.65 × 104 s−1), the present model for TIP4P-
EW water (4.36 × 104 s−1), and the Li and Merz 12−6−4
model for SPC/E water (5.18 × 106 s−1) produced better
results than the others.
For testing in a biology system, we followed the work
provided by Duarte et al.,8 where their parameters were tested
in E. coli Glyoxalase I (GlxI). Here, we tested the present
parameters of Ni2+, Zn2+, Co2+, and Cd2+ with TIP3P water in
the E. coli. GlxI system. All the tested models show an excellent
performance of reproducing the metal center geometry (except
the CN for Zn2+, see Table S9a for Ni2+, Table S9b for Co2+,
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Table S9c for Cd2+, and Table S9d for Zn2+): our calculated
average distances are mostly within 0.1−0.2 Å of the
experimental value. Moreover, unlike the necessary modifica-
tion of the partial charge on the coordinated oxygen atoms of
Glu residues (otherwise, Glu will artificially doubly coordinate
to the metal center by using Duarte parameters) performed in
the Duarte’s work8, the present models produced the metal
center with monodentate Glu residues without the modifica-
tion. We also tested the simulation performance of Li−Merz
12−6−4 parameters4 in the E. coli GlxI system. Without the
modification of the partial charge on the coordinated oxygen
atoms of Glu residues, the metal center showed a similar
geometry with that produced by the present model for
Ni2+, Co2+, and Zn2+, indicating that the Li−Merz 12−6−4
parameters can reproduce the metal center geometry at the
same level of the present model, which can also be achieved
by taking into account the side-chain polarization when using
the Duarte model. However, because of the poor performance
of reproducing the CN in water (CN = 7.5−7.8, shown in
Figure 5b), the Li−Merz 12−6−4 model for Cd2+ cannot
produce the correct CN in the E. coli GlxI system, even when
we modified the Glu side-chain charge distribution as that
performed in the work of Duarte8 (shown in Table S9c).
Note that similar to the results shown in Duarte’s work, the
substitution of the original Ni2+ with Zn2+ in our test also failed
to produce the reported metal center geometry with five ligands
(PDBID: 1FA5)42 during the simulation time, indicating the
complex deactivation mechanism of metal substitution is still
difficult to be studied using such MD simulations.

4. DISCUSSION
Our dummy atom models have several advantages. Although
the present model is developed based on the Duarte model,8
the improvements can be clearly pointed out: (I) The present
work used the two-step TI calculation for the solvation free
energy, leading to the calculated vdW part within the range
from −36 kcal/mol to +2 kcal/mol. This is more accurate than
those in the Duarte work, where the vdW part (called “cavity”
term) was set to be a constant value of +2.5 kcal/mol.8 (II) The
present parameter sets for Cd2+, Hg2+, and Sn2+ have different
charge distributions and different geometries with the original
Duarte dummy models.8 Moreover, the relative errors of the
most IOD values in the Duarte work8 (for TIP3P water) are
bigger than those in this work (see Figure 5a), indicating an
improved accuracy of our parameter sets generated by the
comprehensive search within the parameter space. For the pa-
rameters developed by Li and Merz,4 the relative errors of
CN values are bigger than those in the present work (see
Figure 5b), especially for V2+, Mn2+, Cd2+, Sn2+, and Hg2+.
For our final optimized parameters, the CN values were all
produced correctly, indicating a remarkable advantage of
reproducing CN values for the six-coordinated divalent metal
ions. But for the point charge models provided by Li and Merz,
the CN values of the six-coordinated divalent metal ions can
be accurately reproduced only for Mg2+, Cr2+, Fe2+, Co2+, Ni2+,
and Zn2+.4 The produced ΔGsol for the dummy atom models in
the present work have a slightly larger deviation (unsigned
average error is between 1.1 and 1.3 kcal/mol, shown in Table 4)
than those for the models of Li and Merz (unsigned average
error is about 0.4 kcal/mol);4 but all the relative errors of our
models were controlled under 1%.
Furthermore, by testing the Mg2+ parameters to calculate
the water exchange rate constant, we demonstrated that the
3257
Figure 5. (a) Relative errors of the calculated values of IODRDF for
Mg2+, Mn2+, Fe2+, Co2+, Ni2+, Zn2+ simulated with the parameters for
TIP3P water from Duarte’s work (blue) and the present work (red);
(b) calculated CN values for V2+, Mn2+, Cd2+, Sn2+, Hg2+ simulated
with the parameters for TIP3P, SPC/E, TIP4P-EW, water models
from Li and Merz and the present work.
present model cannot accurately reproduce the water exchange
rate constant. However, because of the failure in reproducing
the rate constant using all the tested models except for the
Allnér model, the present model for TIP4P-EW water can be
acceptable after a fashion, as well as the Duarte model for TIP3P
water and the Li and Merz 12−6−4 model for SPC/E water.
People who want to use the present models to calculate the water
exchange rate constant must take caution.
By testing several metal ions in the biomolecule system,
E. coli GlxI, we demonstrated the actual simulation performance
of the present models. Similar with the results in the previous
work,13 the present models can keep the monodentate
coordination state of Glu side chains without modification of
the charge on the coordinated oxygen atoms of Glu residues,
which cannot be achieved by directly using the Duarte model.
The Li−Merz 12−6−4 model can reproduce the metal center
geometry at the same level of the present model (except for the
tested Cd2+ parameters), which can also be achieved by taking
into account the side-chain polarization when using the Duarte
model. This indicates that the present model has the proper
effect, which is equivalent to the Li−Merz 12−6−4 model
with the ion-induced dipole interaction4 and the Duarte
model taking into account the side-chain polarization,8 on the
octahedral metal center. However, for V2+, Mn2+, Cd2+, Sn2+,
and Hg2+ in the Li−Merz 12−6−4 model, their calculated
geometries in the biomolecule may be incorrect because of
DOI: 10.1021/acs.jctc.6b00223
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Table 4. Simulated IOD, CN, and ΔGsol for the Final Optimized Parameter Sets in Table 3
TIP3P SPC/E TIP4P-EW
IOD (Å) CN ΔGsol (kcal/mol) IOD (Å) CN ΔGsol (kcal/mol) IOD (Å) CN ΔGsol (kcal/mol)
Mg 2+
2.088 6.0 −466.9 2.088 6.0 −471.6 2.092 6.0 −465.7
V2+ 2.189 6.0 −469.5 2.207 6.0 −468.6 2.202 6.0 −469.2
Cr2+ 2.079 6.0 −471.2 2.079 6.0 −474.7 2.079 6.0 −472.5
Mn2+ 2.186 6.0 −453.6 2.193 6.0 −452.4 2.189 6.0 −453.5
Fe2+ 2.113 6.0 −470.2 2.109 6.0 −469.9 2.109 6.0 −470.7
Co2+ 2.103 6.0 −489.6 2.107 6.0 −488.9 2.106 6.0 −488.6
Ni2+ 2.065 6.0 −501.4 2.054 6.0 −502.4 2.051 6.0 −506.8
Zn2+ 2.096 6.0 −497.8 2.093 6.0 −497.6 2.108 6.0 −498.1
Cd2+ 2.301 6.0 −450.3 2.300 6.0 −449.2 2.301 6.0 −450.7
Sn2+ 2.623 6.0 −387.1 2.611 6.0 −387.7 2.610 6.0 −387.2
Hg2+ 2.411 6.0 −452.1 2.410 6.0 −453.0 2.415 6.0 −453.2
average error −0.003 0 0.0 −0.003 0 −0.6 −0.002 0 −0.6
SD 0.007 0 1.6 0.003 0 1.5 0.006 0 1.5
unsigned average error 0.004 0 1.2 0.003 0 1.3 0.005 0 1.1

Table 5. Water Exchange Rate Constantsa (k) of Mg2+ Calculated Using the Present Dummy Model, The Duarte Dummy
Model,8 the Allnér Model,39 and the Li and Merz 12−6−4 Model4
Mg2+ model water model A (s−1) ΔG⧧ (kcal/mol) k (s−1)
Allnér TIP3P 1.68 × 1013
10.07 6.87 × 1005
this work TIP3P 1.99 × 1013 15.51 8.35 × 1001
Duarte TIP3P 1.90 × 1013 11.88 3.65 × 1004
Li and Merz 12−6−4 TIP3P 1.71 × 1013 7.04 1.19 × 1008
this work SPC/E 2.03 × 1013 15.93 4.23 × 1001
Li and Merz 12−6−4 SPC/E 1.71 × 1013 8.89 5.18 × 1006
this work TIP4P-EW 1.82 × 1013 11.75 4.36 × 1004
Li and Merz 12−6−4 TIP4P-EW 1.77 × 1013 7.84 3.16 × 1007
expb 9.9 6.70 × 1005
a
The water exchange rate constant is calculated according the scheme described in section 2.7. bThe experimental value of the water exchange rate
constant of Mg2+ is provided by Bleuzen et al.43

their bad performance of reproducing the CN in water4
(shown in Figure 5b). People who want to use V2+, Mn2+,
Cd2+, Sn2+, and Hg2+ in the Li−Merz 12−6−4 model must take
caution.
The usage of our models is convenient as well. With the
preparation file (.prepi) and the force field modification file
(.frcmod) of the Amber force field provided in the Supporting
Information, the dummy atom model can be directly loaded
into the target system without any additional modifications
to the potentials. Note that the model parameters of Mg2+ for
TIP3P water is not identical to that provided in our previous
work13, because of using different parameter generation
approaches. But both of them can produce the coordination
geometry and solvation free energy with the relative error
under 1%. Therefore, both the two models of Mg2+ are well-
optimized and applicable.
On the other hand, the CN values produced during
the parameter space scanning can be greater than six (see
section 3.1), indicating the capacity of our model to accurately
reproduce the CN values of the nonhexacoordinate metal ions.
octahedral dummy model is inadequate to simulate the metal
ions with the CN less than 6 (such as Be2+ with a CN of 4, or
Zn2+ with a CN of 5).
5. CONCLUSIONS
This work provided three sets of nonbonded dummy atom
model parameters of 11 common divalent metal cations (Mg2+,
V2+, Cr2+, Mn2+, Fe2+, Co2+, Ni2+, Zn2+, Cd2+, Sn2+, and Hg2+)
optimized for the TIP3P, the SPC/E, and the TIP4P-EW water
models. These three sets of parameters were generated through
a parameter generation procedure using the experimental
solvation free energies revised by an accurate proton hydra-
tion free energy (−265.9 kcal/mol). All the parameters can
accurately reproduce the experimental values of metal−oxygen
distance, coordination number (especially for V2+, Cd2+, Sn2+,
and Hg2+) and solvation free energy in water. Moreover, the
calculated solvation free energies for all the models are
independent of the simulation methodology. The models in
this work provide a good choice for researchers to study these
divalent metal cations in silico with exchangeable ligands for
studying the metal-containing biological systems.

■
For example, the Ca2+ parameters of the current octahedral
model for TIP3P water is [R = 1.1729 Å; ε = 6.7992 kcal/mol]
with the MC-D bond length of 0.9 Å and the dummy atom ASSOCIATED CONTENT
charge of 0.5 e. This set of parameters can produce the CN *
S Supporting Information

of Ca2+ to be 8.0, IOD to be 2.47 Å, and ΔGsol to be
−390.42 kcal/mol, where the experimental CN44 is 8, IOD44 is
2.46 Å, and ΔGsol is −390.6 kcal/mol (revised according to
the method described in section 2.2). However, the current
3258
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jctc.6b00223.
Supporting tables and figures for the calculation details,
and the examples for the model preparing files (PDF)
DOI: 10.1021/acs.jctc.6b00223
J. Chem. Theory Comput. 2016, 12, 3250−3260
Journal of Chemical Theory and Computation
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: twtan@mail.buct.edu.cn.
Funding
All the simulations were supported by CHEMCLOUDCOM-
PUTING. This work was supported by the National Basic
Research Program of China (973 program) (2013CB733600),
the National Nature Science Foundation of China
(21436002,21390202), and the China Postdoctoral Science
Foundation (2015M580993).
Notes
The authors declare no competing financial interest.
■
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3260 DOI: 10.1021/acs.jctc.6b00223

J. Chem. Theory Comput. 2016, 12, 3250−3260