Fluid Phase Equilibria 472 (2018) 85e93

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Fluid Phase Equilibria

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / fl u i d

Using molecular dynamics simulations to predict the effect of

temperature on aqueous solubility for aromatic compounds

lica Fierro b, Loreto M. Valenzuela a, c, Jose
Raimundo Gillet a, Ange
rez-Correa a, *

R. Pe
a
Department of Chemical and Bioprocess Engineering, School of Engineering, Pontificia Universidad Cato
lica de Chile, Avda. Vicun~ a Mackenna 4860,
Santiago, Chile
b
lica de Chile, Avda, Vicun
Institute of Biological and Medical Engineering, School of Engineering, Pontificia Universidad Cato ~ a Mackenna 4860, Santiago,
Chile
c
Bioorganic and Molecular Modeling Lab, Organic Chemistry Department, Faculty of Chemistry, Pontificia Universidad Cato
lica de Chile, Avda. Vicun
~a
Mackenna 4860, Santiago, Chile

a r t i c l e i n f o a b s t r a c t

Article history: Since polyphenols are highly bioactive, their separation and purification are active research topics. In the
Received 20 February 2018 optimization of such processes, the trend of solubility at different conditions is of major interest,
Received in revised form although obtaining experimental solubility data for polyphenols is lengthy and costly. A simple and
7 May 2018
previously explored thermodynamic integration (TI) procedure was applied to estimate the Gibbs hy-
Accepted 11 May 2018
Available online 12 May 2018
dration free energies at different temperatures for benzoic acid, (þ)-catechin and toluene. These hy-
dration energies were compared with experimental solubilities. An extensive test with 10 replications
comprising a total of 200 molecular dynamics (MD) TI simulations was conducted. Linear trends were
Keywords:
Polyphenols
observed for the estimated Gibbs hydration free energy at different temperatures. Electrostatic contri-
Solid-liquid extraction butions showed a strong effect for the studied polyphenols due to hydrogen bonds. Lennard-Jones (LJ)
Solubility contributions to hydration free energies were small, being more significant for toluene due to cavity
Hydration free energy formation. The estimated Gibbs free energy of hydration presented an exponential trend for benzoic acid
Molecular dynamics simulations and (þ)-catechin when compared to experimental solubility data. These trends were fitted to an
Thermodynamic integration empirical expression. To understand the physical meaning of the empirical fitting parameters, the effect
Solvation of temperature in the sublimation enthalpy and in the entropy of the solid solute should be estimated.
© 2018 Elsevier B.V. All rights reserved.

1. Introduction for the optimization of these processes. Obtaining solubility data of

Polyphenols are a well-studied and broad family of bioactive
natural compounds found in plants and known for their antioxi-
dant, vasodilatory, anti-carcinogenic, anti-inflammatory, immune-
stimulating, anti-allergic and antiviral properties [1]. There is
much interest in industry and academia for extracting these com-
pounds from their natural sources to use them for the preparation
of new nutraceuticals, functional food ingredients, pharmaceuti-
cals, and cosmetic products. Extraction processes can be optimized
if the solubility of the desired compound in the extraction solvent is
known at different temperatures and pressures. Specially, the trend
of solubility at different conditions provides sufficient information
* Corresponding author.
E-mail addresses: rgillet@uc.cl (R. Gillet), afierroh@uc.cl (A. Fierro), lvalenzr@

rez-Correa).
ing.puc.cl (L.M. Valenzuela), perez@ing.puc.cl (J.R. Pe
polyphenols by means of experiments is complex, therefore,
extraction processes of polyphenols are commonly optimized by
using the experimental response surface method [2,3], which is
highly demanding in terms of cost and time. Reliable predictions of
the effects of temperature and pressure on the solubility of poly-
phenols would simplify, accelerate, and reduce the costs of the
development of new natural products.
To accurately predict solubility, the non-ideality in the mixture
should be considered. The most commonly used methods for this
task are activity coefficient models [4e8], nevertheless, these
models are limited since they require experimental solubility data
as input [9]. Quantitative structure-property relationship (QSPR)
methods have been widely used as well. They are based in statis-
tical relations between experimental solubility data and molecular
properties such as electronic and topological evaluations, hydro-
philicity/hydrophobicity calculations, molecular surface area,
among other properties [10e13]. However, these computational

https://doi.org/10.1016/j.fluid.2018.05.013
0378-3812/© 2018 Elsevier B.V. All rights reserved.
86 R. Gillet et al. / Fluid Phase Equilibria 472 (2018) 85e93

methods need experimental solubility data for many compounds

and do not consider the exact interaction between solute and sol-
vent. Molecular dynamics (MD) and Monte Carlo (MC) simulations
have proven to be more suitable computational tools for the study
and prediction of solubility. Unlike activity coefficient and QSPR
methods, MD and MC consider a detailed description of the atomic
and molecular interaction without simplifications and without Fig. 1. Benzoic acid (C7H6O2), (þ)-catechin (C15H14O6) and toluene (C7H8) molecules.
requiring experimental solubility data.
Two MD and MC methods have been applied for solubility
compound which presents structural similarity with benzoic acid,
predictions [9,14e30]. In the chemical potential route (CPR), solu-
however, its aqueous solubility is much lower.
bility is determined as the solute concentration in solution at which
The remaining sections of this paper are organized as follows:
the chemical potential of the solution is equal to that of the crystal
Section 2 contains computational details and explains the methods
solid [14e26]. In the alternative direct coexistence method (DCM),
used in our study. In Section 3 we present and discuss our results.
the solution is brought into contact with the solid crystal, and the
Our findings are summarized in Section 4.
solubility corresponds to the equilibrium solute concentration
[27e30]. The main limitation of DCM and CPR methods, is the
2. Methods and computational details
scarcity of accurate force fields available for crystalline compounds
[14]. In addition, computing absolute solid free energies of molec-
2.1. Software packages
ular solids, although straightforward, is cumbersome [14]. More-
over, the obtained solubility values strongly depend on the force
MD simulations were carried out in the NAMD (NAnoscale
field used [15]. For example, several research groups employing
Molecular Dynamics) v2.12 simulation package [40]. To perform
different CPR or DCM methods have reported widely different NaCl
thermodynamic integration (TI) [38] calculations, we employed the
aqueous solubilities at ambient conditions [31]. To improve MD
TI method [41] included in the NAMD v2.12 package. VMD (Visual
solubility calculations, the estimation of solid phase properties
Molecular Dynamics) v1.9.2 [42] was used to create initial system
should be improved and more accurate force field parametrizations
configurations and to represent and study molecular structures, as
for crystalline compounds should be derived.
well as molecular motions of the systems.
Two decades ago, Lipinski et al. [32] reviewed solubility pre-
diction methods, and suggested that solubility is the result of the
complex interplay between different energy contributions such us 2.2. Models
(1) the energy required to disarray the solute crystal lattice to bring
its molecules into solution (generally referred to as sublimation free All force field parameters, except for the atomic point charges of
each solute, were taken from the CHARMM force field [43]. This
energy, Dsub G), (2) the energy associated to the interactions be-
tween solute and solvent molecules in solution, and (3) the energy force field has been extensively used to model pharmaceutical and
natural compounds. Point charges were calculated quantum-
required to form a cavity in the solvent, into which the solute
molecule is hosted. In this study we applied MD simulations to mechanically at the Hartree-Fock 6-31G* basis set [44] with the
Spartan’10 v1.1.0 software [45]. Mol2 archives containing the
analyze the effect of temperature on solubility, focusing on the
latter two contributions, which are accounted for by the hydration calculated charge values (support information) were extracted
from the software, and then, these charge values were inserted into
free energy term (Dhyd G).
We studied the effect of temperature variations in hydration the input files.
Water molecules were represented using the TIP3P model [46],
free energy and compared the calculated trends with experimental
solubility data. There are several studies that used MD and MC which is probably the most used water model for biomolecules
simulations to calculate hydration free energies. For example, simulations. In addition, TIP3P simulations provided accurate pre-
Garrido et al. [33] calculated hydration free energies and 1-octanol dictions of hydration free energy for a wide set of compounds [35],
solvation free energies to predict partition coefficients, which along and was also used to infer relative solubilities [37]. Moreover, since
with the experimental melting point of a compound, can be used to TIP3P is the default solvation model in NAMD, it is straightforward
predict its solubility [34]. Mobley et al. [35] applied a simple MD to apply.
method using the explicit TIP3P (Three-Point Transferrable Inter- CHARMM force-fields use harmonic bonds and angles of the
molecular Potential) water model [36] to predict the hydration free form
energies of 504 neutral compounds. Chebil et al. [37] also applied X
MD with the explicit TIP3P water model and solvation free energy Ebond ¼ kbi ðbi  b0i Þ2 (1)
i2bonds
calculations, to estimate the solubilities of quercetin on different
solvents using a single experimental solubility. In our study we
and
applied MD simulations with the explicit TIP3P water model and
the thermodynamic integration (TI) method [38] to calculate hy- X 2
Eangle ¼ kqi ðqi  q0i Þ (2)
dration free energies at different temperatures. In addition, we i2angles
compared the calculated hydration free energies with the experi-
mental aqueous solubility of a set of compounds. The impact of the where kbi and kqi are force constants for the bonds and angles har-
hydration free energy term in the variation of solubility with monic potentials, respectively. b0i and q0i are equilibrium bond
temperature has not been analyzed before using MD simulations. lengths and angles. A truncated Fourier series models dihedral
To validate our results, each MD simulation was replicated 10 times, angles of the form
yielding more than 200 TI-MD simulations. Three compounds were
X
chosen for this study, (þ)-catechin, benzoic acid and toluene Edih ¼ kfi ½1 þ cosðni fi  di Þ (3)
(Fig. 1). (þ)-Catechin and benzoic acid are part of the polyphenol i2dih
family [39]; (þ)-catechin is a flavonoid while benzoic acid is a
precursor of the phenolic acids [1]. Toluene is an aromatic where kfi are force constants, besides ni , fi and di are dihedral
 R. Gillet et al. / Fluid Phase Equilibria 472 (2018) 85e93
period, angle, and phase, respectively. Short-range and long-range
interactions are modeled using 12-6 Lennard-Jones (LJ) potentials
and Coulomb potentials, of the form
8 2 9 ticle Mesh Ewald summation [55] with a grid size equal to the size
!12 !6 3
X X< Rmin Rmin qi qj =
εij 4 5þ
ij ij ij
ELJþC ¼ 
: rij rij 4pε0 rij ;
i j>i
where εij and Rmin
ij are LJ parameters, qi and qj are partial charges
and rij is the distance between atoms i and j. Unlike-atom in-
teractions are computed using geometric mean combining rules for
the εij parameters, and average combining rules for the Rmin ij
parameters,
pffiffiffiffiffiffiffi
εij ¼ εi εj
Rmin
i þ Rmin
j
Rmin
ij ¼
2
In the CHARMM forcefield, 1e4 intramolecular non-bonded
interactions are handled by scaling down the electrostatic inter-
action by a factor of 1.0. Regarding LJ interactions, a secondary set of
parameters is included in the force field for specific atoms. In such
cases, 1e4 intramolecular LJ interactions are modified by using the
secondary LJ parameters. In the remaining cases, 1e4 LJ interactions
are scaled down by a factor of 1.0 since their spatial relationship is
already influenced by the internal terms, including the dihedral
term [47].
2.3. Simulation details
For the three compounds, isobaric aqueous solubility data at
different temperatures was retrieved from literature to subse-
quently compare it to the simulation results. Cuevas-Valenzuela
et al. [48] measured benzoic acid and (þ)-catechin solubilities at
different temperatures and atmospheric pressure (101.325 kPa),
while Miller & Hawthorne [49] measured toluene solubilities at
different temperatures and 50 bar (5 MPa). The experimental data
is presented as plots of solubility against temperature in supporting
information. In this work, simulations were set up to reproduce the
same conditions as experimental references, particularly the pres-
sure and temperature, and in such conditions, the Gibbs hydration
free energy was estimated for each compound.
MD simulations were conducted using the NAMD v2.12 simu-
lation package. To build the systems, each solute was submerged in
a pre-equilibrated solvent box of 3 nm of side, which included
approximately 800 water molecules. This was done using the Sol-
vate 1.5 plugin [50], which is incorporated in VMD (Visual Molec-
ular Dynamics) v1.9.2 package [42]. Firstly, each system was pre-
equilibrated to reach temperatures and pressures in accordance
to the mentioned experimental conditions. To achieve this, each
system was subjected to an energy minimization of 0.05 ns using
the conjugate gradient algorithm [51], followed by an NPT equili-
bration for 1 ns. Afterwards, hydration free energies were esti-
mated for each compound at each of the conditions following the TI
procedure described by Garrido et al. [52], whom were able to
accurately predict hydration free energies without any experi-
mental information and without any fitting of parameters.
MD simulations were performed using periodic boundary con-
ditions in all directions, and Newton's equations of motion for all
the species were integrated using the leap-frog dynamic algorithm
[53] with a timestep of 2 fs (2$106 ns). Temperature and pressure
were kept constant using Langevin dynamics and the Langevin
piston method, respectively [54]. A frictional constant of 1 ps1 was
used for the temperature control Langevin method. For the
87
Langevin piston method, a period of 100 fs and a decay of 150 fs
were selected. LJ interactions were truncated using a cutoff radius
of 1.2 nm. Electrostatic interactions were calculated using the Par-
of each simulation box.
(4) In the TI simulations, 50 different l values uniformly distributed
between 0 and 1 were used. Each l step was simulated through 0.1
ns and the energy was measured each 20 fs (2$105 ns), summing
5000 energy measurements for each l step. The last 20,000 fs (1000
energy measurements) of each l step were collected, and the en-
ergy was averaged. Along with the average energies, standard de-
viations for the energy measurements were calculated in each l
step and were later used to calculate the error from propagation of
uncertainty. Following the methodology of Garrido et al. [56], LJ
(5) interactions were interpolated using a soft-core potential with a
soft-core parameter of 0.5.
This procedure was implemented for all compounds at each
(6) temperature. The TI procedure was repeated 10 times to assure the
consistency and repeatability of the results. Since 20 simulations
were required for each replica (9 temperatures for benzoic acid, 6
temperatures for (þ)-catechin and 5 temperatures for toluene), a
total of 200 TI-MD simulations were conducted in a multiprocessor
computer with 12 processing nodes.
2.4. Output analysis
The curves of energy versus lambda retrieved from the simu-
lations were integrated numerically using a modified version of the
namd_ti.pl perl script that can be found in the NAMD website [57].
The most common approach for integrating the free energy
gradient in TI is the trapezoidal rule, nevertheless, it has been
shown to lead to systematic errors [58e60]. Conversely, namd_ti.pl
script uses cubic spline interpolation for the numerical integration.
In addition, we added to the script a feature to compute standard
deviations of the free energies. To do this, we applied the general
formula for propagation of uncertainty [61], which defines the
uncertainty df of a function f of n independent variables
ðx1 ; x2 ; … ; xn Þ as follows:
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
 2  2
vf vf
df ¼ dx1 þ … þ dxn (7)
vx1 vxn
Finally, the calculated solvation free energies averaged from the
10 replicas were compared with experimental solubility data. In
addition, to assess the variation of cavity formation terms at
different temperatures, hydration shells of each compound were
analyzed by means of radial distribution functions (RDF) at the
equilibrium state prior to each TI run.
3. Results and discussion
3.1. Hydration free energy at different temperatures
Calculated average hydration free energies and their errors for
each replica were compared. The results from the 10 repetitions
were gathered into average values along with their respective er-
rors, and their trends were analyzed in graphs of hydration free
energy against temperature. None experimental measurements of
absolute hydration free energy were found in literature for the
selected compounds at the selected conditions (i.e. 0.1 MPa for
benzoic acid and (þ)-catechin; 5 MPa for toluene), therefore the
accuracy of our hydration free energy calculations could not be
validated directly against experimental data. Toluene's hydration
free energy has been reported to take a value of 0.77 kcal mol1
(3.22 kJ mol1) [62e64] at ambient conditions (293 K, 0.1 MPa),
88 R. Gillet et al. / Fluid Phase Equilibria 472 (2018) 85e93

(a) 278 283 294 300 308 318 327 337 341 278 283 294 300 308 318 327 337 341
100 100

LJ Contribution to ΔhydG (kJ∙mol-1)

El. Contribution to ΔhydG (kJ∙mol-1)
0 0
-100 -100
-200 -200
-300 -300
-400 -400
-500 -500
-600 -600
-700 -700
-800 -800
Temperature (K) Temperature (K)
R1 R2 R3 R1 R2 R3

278 283 298 308 325 331 278 283 298 308 325 331
(b)100 100

LJ Contribution to ΔhydG (kJ∙mol-1)

0 0
El. Contribution to ΔhydG (kJ∙mol-1)

-100 -100
-200 -200
-300 -300
-400 -400
-500 -500
-600 -600
-700 -700
-800 -800
Temperature (K) Temperature (K)
R1 R2 R3 R1 R2 R3

298 323 373 423 473 298 323 373 423 473
(c)100 100
LJ Contribution to ΔhydG (kJ∙mol-1)
El. Contribution to ΔhydG (kJ∙mol-1)

0 0
-100 -100
-200 -200
-300 -300
-400 -400
-500 -500
-600 -600
-700 -700
-800 -800
Temperature (K) Temperature (K)
R1 R2 R3 R1 R2 R3

Fig. 2. Average electrostatic and LJ contributions to the Gibbs hydration free energies calculated for benzoic acid (A), (þ)-catechin (B) and toluene (C) at each simulation tem-
perature for three replicas. Error bars correspond to the errors calculated by propagation of uncertainty.

while we calculated a value of 47.78 kJ mol-1 at ambient temper- significant variations with changing temperatures, although these
ature and 5 MPa. Even though these need to be corrected by the contributions present slightly more variability between replicas than
pressure difference, our estimations were higher than the usual those of electrostatic contributions.
hydration free energy values, which might well be explained by the Fig. 3shows for each compound the trends of electrostatic
water model that we used. Nevertheless, our interest was esti- contributions, LJ contributions, and Gibbs hydration free energies
mating the relative differences between hydration free energies at calculated at different simulation temperatures and averaged from
different temperatures rather than obtaining accurate predictions.
Fig. 2 shows the results of three replicas along with their errors;
the remaining results are tabulated in our supporting information. Table 1
We also include global error estimates from the 10 individual replicas Hydrogen bond donor/acceptor groups count, polarizability and dipole moment
at each temperature as supporting information, to verify the consis- of each solute compound. Properties were determined using the software
Spartan ’10 v1.1.0.
tency between both global errors and the errors from individual
replicas (see Table 1 e in supporting information). The figure shows Compound Hydrogen bond Polarizability Dipole moment
highly consistent simulations, with small variations between donor/acceptor count
different replicas and low standard deviations. Statistically significant Benzoic acid 1/1 48.76 2.16 debye
differences are observed in electrostatic contributions calculated at (þ)-Catechin 5/6 60.21 0.82 debye
different temperatures. LJ contributions show non-statistically Toluene 0/0 47.84 0.27 debye
 R. Gillet et al. / Fluid Phase Equilibria 472 (2018) 85e93 89

the 10 replicas. Errors determined by propagation of uncertainty
are presented with bars.
In the CHARMM force field, hydrogen bonds are included in the
electrostatic interaction term along with coulombic attractions and
repulsions. LJ term accounts for the weak dipole attraction between
distant atoms and the hard-core repulsion between neighbor atoms
that is related to the formation of cavities. It is clear from Fig. 3 that
the trend in hydration free energy is basically of electrostatic origin.
Clear trends were observed for benzoic acid and (þ)-catechin,
while a small variation was observed for toluene. This might be
explained by the presence of functional groups that usually behave
as donors or acceptors of hydrogen bonds in the studied poly-
phenols; these interactions have large contributions to the free
energy. Accordingly, hydrogen bonds donor and acceptor groups
were counted for each compound (Table 1) using the software
Spartan ’10 v1.1.0 [45]. It was observed that higher donor/acceptor
counts lead to more pronounced trends in the electrostatic con-
tributions against temperature. Moreover, the donor/acceptor
count informed that toluene does not act neither as an acceptor nor
donor of hydrogen bonds, which was reflected in its small elec-
trostatic contribution variation. This small variation might be due
to a dipole moment (Table 1) effect in electrostatic contributions,

(a) 0 (a) 1.2

-200
Elec. Contribution to ΔhydG

1
-400

g(r) (g ∙ cm-3)
0.8
-600 278 K
(kJ ∙ mol-1)

283 K
0.6 294 K
-800
300 K
toluene 0.4 308 K
-1000
benzoic acid 318 K
-1200 0.2 327 K
catechin 337 K
-1400 341 K
0
270 330 390 450
Temperature (K) 0 2 4 6 8 10
r (Å)
(b) 0 (b) 1.2
-200
LJ Contribution to ΔhydG

1
-400
g(r) (g ∙ cm-3)

0.8
(kJ ∙ mol-1)

-600

-800 0.6
278 K
toluene 283 K
-1000 0.4
benzoic acid 298 K
-1200 308 K
catechin 0.2 325 K
-1400 331 K
270 330 390 450 0
Temperature (K) 0 2 4 6 8 10
r (Å)
(c) 0
(c) 1.2
-200
ΔhydG (kJ ∙ mol-1)

1
-400
g(r) (g ∙ cm-3)

0.8
-600

-800 0.6
toluene
-1000 0.4 298 K
benzoic acid 323 K
-1200 373 K
catechin 0.2 423 K
-1400 473 K
270 330 390 450 0
Temperature (K) 0 2 4 6 8 10
r (Å)
Fig. 3. Calculated electrostatic (Elec.) and LJ contributions, and total Gibbs free energy
of hydration (DhydG) at different temperatures for benzoic acid (a), (þ)-catechin (b) and Fig. 4. Solute (excluding hydrogens) e water oxygen RDFs calculated from the equi-
toluene (c). Error bars correspond to the standard deviation of each result, calculated librium state prior to each TI run for benzoic acid (a), (þ)-catechin (b) and toluene (c)
by propagation of uncertainty. Dotted lines correspond to adjusted linear trends to at each temperature. Noticeable variations in the height of toluene's RDFs illustrate a
each data set. temperature-dependence of its hydration shell size.
90 R. Gillet et al. / Fluid Phase Equilibria 472 (2018) 85e93

which was minor compared to the effect of hydrogen bonds. Starting from the thermodynamic definition of solid-liquid
Toluene and benzoic acid show a small, but statistically signifi- equilibrium and considering an infinitely diluted system, the sol-
cant, increasing trend in their LJ contributions with temperature, ubility of a compound can be related to its hydration free energy
while (þ)-catechin does not show any trend. These contributions using the following expression,
are due to vdW attractive dispersion interactions and cavity for-  
mation terms. Van der Waals (vdW) attractive dispersion in- n1 ðT; pÞf2s ðT; pÞ Dhyd G
x2 ¼ exp  (11)
teractions are related to the polarizability of each molecule RT RT
(Table 1). Contrary to the observed trend in LJ contributions,
(þ)-catechin presents the highest polarizability value, while where n1 is the intensive molar volume of the solvent, f2s ðT; pÞ is the
toluene and benzoic acid present similar lower values. Therefore, fugacity of the solid (compound 2) at pressure p and temperature T
vdW attractive dispersion interactions seems not significant and LJ and R is the universal gas constant. Equations (10) and (11) look
contribution variations would mainly be due to cavity formation. To n ðT;pÞf s ðT;pÞ
1,
similar, with parameters A and B equivalent to 1 RT2 and RT
assess the relative magnitude of the variation in the cavity forma-
respectively. However, we compared the solubility data with the
tion contributions at different temperatures, the hydration shells of Dhyd G
each compound were analyzed using radial distribution functions term RT at different temperatures (supporting information) and
observed that parameter B is not equivalent to RT 1 . Moreover, the
(RDF) of oxygen atoms in the water molecules surrounding the
solutes (Fig. 4). In this case, trajectories of the pre-equilibration s
fugacity of the solid, f2 ðT; pÞ, should present significant variations
runs were considered rather than the trajectories of TI runs, since with temperature that might be expressed linearly (in parameter A)
the hydration shell is formed at the equilibrium state which pre- or exponentially (in parameter B). Prausnitz et al. [66] derived the
cedes the solute annihilation. following expression for the fugacity of a solid or a liquid,
RDFs in Fig. 4 show a noticeable temperature-dependence in the
 !
hydration shell size of toluene, while no significant variation is ns p  psat
observed for the studied polyphenols. Since the free energy of fis ðT; pÞ ¼ psat
i exp i
(12)
RT
cavity formation in water is proportional to the surface area of the
cavity [65], it can be inferred that the cavity formation term
where psat
i is its vapor pressure at temperature T, ns is the molar
dependence with temperature is stronger for toluene than for
volume of the solid at temperature T and pressure p, and R is the
benzoic acid and (þ)-catechin. Therefore, variations in LJ contri-
universal gas constant. This expression is valid only at conditions
butions at different temperatures were mainly associated to a
far from the critical point, where the solid phase can be considered
varying cavity formation term, which was only important for
as incompressible. Also, it is required that the saturation pressure of
toluene (non-polar).
the solid is lower than 1 bar, which normally is the case of com-
pounds which behave as solids or liquids at normal conditions. The
3.2. Comparison between the MD results and experimental vapor pressure of a solid or liquid at temperature T can be deter-
solubility data mined using the Clausius-Clapeyron relation,
   
Fig. 5 compares the calculated hydration free energies at DHis ðTÞ 1 DSsi ðTÞ
psat
i ¼ exp  þ (13)
different temperatures with experimental solubility data [48,49] R T R
(Fig. 5).
Exponential shapes were observed for the Gibbs free energy of where DHis ðTÞ and DSsi ðTÞ are the sublimation enthalpy and entropy
hydration of (þ)-catechin and benzoic acid (Fig. 5), while no trend of the solid, respectively at temperature T and R is the universal gas
was shown for toluene (supporting information). Calculated values constant. Substituting equations (12) and (13) in equation (11), the
showed small errors and the differences in the trends were statis- following expression is derived,

  

0 DHs ðTÞ DSs ðTÞ 1

ns ðT;pÞ pexp  2
R
1
T
þ 2
R
   
DH2s ðTÞ DSs2 ðTÞA
exp@
Dhyd G 1
RT  RT  R T þ R n1 ðT; pÞ
x2 ¼ (14)
RT

tically significant. As discussed in Section 3.1, the marked trends
that are observed in polyphenol's results are due to an important
effect in electrostatic contributions at different temperatures,
which are strongly related to hydrogen bonds. These trends were
fitted to an exponential function,
 
x ¼ A exp  B$Dhyd G
Therefore, to understand the physical meaning of parameters A
and B and, moreover, to predict their values, expressions of the
variation of sublimation enthalpies and entropies of the solid at
different temperatures are needed. It seems that these values do not
need to be calculated accurately to get good estimations of the sol-
ubility variation of polyphenols with temperature, since we observed
that inaccuracies in the Dhyd G calculations did not prevent us for
(10) obtaining good estimations of its variations with temperature.

where A and B are fitting parameters. To understand the physical 4. Conclusions

meaning of these parameters, we will now examine a similar
equation that has been proposed [18] for the relation between In this article, we have reviewed the state of art in solubility
solubility and hydration free energy. prediction from MD simulations and observed that a current
 R. Gillet et al. / Fluid Phase Equilibria 472 (2018) 85e93 91

0.003
benzoic acid
catechin
0.0025

Solubility (mol ∙ mol-1)

0.002 y = 2E-06e-0.006x y = 1E-05e-0.009x
R² = 0.872 R² = 0.9694
0.0015

0.001

0.0005

0
-1300 -1100 -900 -700 -500 -300
ΔhydG (kJ ∙ mol-1)

Fig. 5. Calculated free energies of solvation (DhydG) vs. experimental solubility at different temperatures. Benzoic acid and (þ)-catechin show exponential trends (adjusted; dotted
lines). Toluene is not shown since no trend was observed. Horizontal error bars correspond to the standard deviations of the free energy calculations, obtained by propagation of
uncertainty. Vertical error bars correspond to the reported errors in each experimental reference.

limitation in this field is the inaccuracy of solid state simulation kf Dihedral angle constant (kJ mol1)
results. As a result, a method for studying the effect of temperature n Dihedral period
in solubility by means of hydration free energy calculations has p Pressure (kPa)
been proposed. psat Vapor pressure (kPa)
Even though our hydration free energy predictions were not q Partial charge in units of jej
accurate, our results were robust, and, in the case of polyphenols, r Interatomic distance (Å)
were able to yield exponential fittings to the relation between R Ideal gas constant (kJ mol1 ∙ K1)
solubility and hydration free energy, just as it is proposed in ther- Rmin Lennard-Jones parameter (Å)
modynamic models. We observed that the fitting parameters might T Temperature (K)
be related to the sublimation enthalpy and entropy of the solid x mole fraction
solute. A complementary study comprising solid state simulations
should be carried out to understand the physical meaning of these Greek letters
parameters. There, the effect of temperature in the sublimation Dhyd G Gibbs hydration free energy (kJ mol1)
enthalpy and entropy of the solid solute should be studied. Even if DHs ðTÞ Sublimation enthalpy of the solid (kJ mol1)
the results of such study were not accurate (which is common in DSs ðTÞ Sublimation entropy of the solid (kJ mol1 ∙ K1)
the field of solid state simulations), the retrieved trends might be d Dihedral phase (rad)
robust and meaningful, just as we observed in this work. ε Lennard-Jones parameter (kJ mol1)
ε0 Permittivity of vacuum (C2$N1 ∙ m2)
Acknowledgements q Covalent angle (rad)
q0 Harmonic equilibrium angle (rad)
This research was part of a master thesis and was funded by l Coupling parameter for thermodynamic integration
project “ANILLO ACT 1105/2012” and FONDECYT 1161375. We are (scalar)
grateful to Andre
s Mejia for recommendations and suggestions m Chemical potential (kJ mol1)
during the course of this work; and to the National Institutes of n Intensive molar volume (m3 ∙ mol1)
Health for the use of the software NAMD v2.12. p Pi number
f Dihedral angle (rad)

Appendix A. Supplementary data

Abbreviations
LJ Lennard-Jones
Supplementary data related to this article can be found at
MC Monte Carlo
https://doi.org/10.1016/j.fluid.2018.05.013.
MD Molecular Dynamics
NAMD NAnoscale Molecular Dynamics
List of symbols NPT Ensemble: fixed number, pressure and temperature
RDF Radial distribution function
Å angstrom (1 Å ¼ 0.1 nm) TI Thermodynamic Integration
b Bond length (Å) TIP3P Three-Point Transferrable Intermolecular Potential
b0 Harmonic bond equilibrium length (Å) vdW van der Waals
f2s ðT; pÞ fugacity of the solid (kPa) VMD Visual Molecular Dynamics
G Gibbs free energy (kJ mol1)
H Hamiltonian function References
kb Harmonic bond constant (kJ ∙ Å2 ∙ mol1)
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