Jul 2026· Journal of Chemical Theory and Computation· 0 citations· 55 references
Medicine
Abstract
Free energies of solvation (ΔGsol) in a prototypical liquid alkane, cyclohexane, have been computed for 101 organic molecules at 25 °C. Monte Carlo statistical mechanics (MC) was used with free-energy perturbation theory (FEP) and both OPLS united-atom (UA) and all-atom (AA) force fields. Updated OPLS-UA parameters are provided along with thermodynamic results for 23 liquid alkanes; the modifications make the UA and AA force fields fully compatible. The average errors for ΔGsol in comparison to experimental data are ca. 0.5 kcal/mol for both force fields. This supports general use of the UA model, since it reduces the required computation times by 5-10-fold. The largest errors are about 1 kcal/mol and occur for small molecules with relatively large dipole moments and for perfluorocarbons. The former case is attributable to the lack of solvent-polarization in the force fields, and the latter issue can be remedied by reducing the Lennard-Jones well depth for the interaction of saturated carbon and fluorine. Results for free energies of hydration are also provided for the 101 solutes in TIP4P water and the average error is again 0.5 kcal/mol. The combined results provide cyclohexane/water free energies of transfer with average errors of 0.7 kcal/mol. In conjunction with prior results for solvation in benzene and perfluorobenzene, the 0.5 kcal/mol level of accuracy seems general for the performance of current generation, nonpolarizable force fields. Implications for modeling hydrophobic effects and protein-ligand binding are also considered.
We develop and validate a new united-atom (UA) model for alkylamines under the polarization consistent approach (PolCA) formalism. Making use of recent theoretical developments in the treatment of polarization effects, we apply post facto polarization corrections to improve the accuracy and transferability of the model. We parameterize the model against the experimental density, enthalpy of vaporization and dielectric constant of selected amine molecules. The model is then validated against self-solvation free energies and solvation free energies in n-hexadecane. Overall, the new PolCA model outperforms the state-of-the-art GROMOS UA model, eliminating systematic deviations in that model's predictions for methylamine. We also present further evidence that polarization energy corrections are required when transferring the model from pure liquids to mixtures, particularly when the solute and solvent have significantly different polarity. The main shortcoming of the model is the lack of accuracy in predictions of the dielectric constant of small amine molecules, which is overestimated relative to experimental data. We show that this is likely due to the effective dipole moment of practically all previous non-polarizable models (including PolCA) being higher than the real dipole moment of amines in the liquid phase, which we estimated using the recent Self-Consistent Electrostatic Embedding approach.
M. Barrera, J. R. Gomes, Miguel Jorge· Physical Chemistry, Chemical...· 0 citations
The generalized PB theory is validated using a perturbed two-atom system and a diverse set of proteins with different structures in vacuum and water, demonstrating its accuracy and robustness, regardless of the choice of sharp-interface and diffuse-interface PB models and different numerical solvers.
Matthias Dogbatsey, Yuanzhen Shao, Emil Alexov et al.· 0 citations
Supercritical CO2 is a highly efficient solvent for the development of more environmentally benign chemical processes. It is crucial to predict its solvation properties─the solvation free energy and the solvation structure─both accurately and at low computational cost. We show here that classical density functional theory (cDFT) can reproduce the solvation properties obtained from conventional molecular simulations, while requiring a computational effort that is several orders of magnitude lower. This excellent agreement is achieved using a molecular cDFT formalism based on a density that depends on both the positions and orientations of CO2 molecules in the vicinity of the solute. We further examine several levels of approximation for the excess free-energy functional in cDFT and demonstrate that the homogeneous reference fluid approximation is sufficient to recover the molecular dynamics (MD) benchmark results. These findings open the way to extending molecular cDFT to other thermodynamic conditions.
Mohamed Houssein Mohamed, Odette Tannous, Camille Muller et al.· Journal of Physical Chemistr...· 0 citations
A fast pipeline based on the OPLS-AA force field is presented that enables the automated calculation of non-bonding intermolecular (dimer) interaction energies derived from a set of small organic (monomer) molecules. To calculate the non-bonding contributions, optimized geometries of the monomer molecules as well as their OPLS-AA van der Waals and atomic partial charge parameters are required. The key advantage of the new pipeline lies in its fast, highly parallelized in-memory computations without slow I/O operations, which make it possible to thoroughly process comparatively large numbers of (more than a hundred) monomer molecules within acceptable time frames (hours and days): Compared to an analogous, more versatile, and comprehensive approach, the new computational scheme delivers comparable results while being more than two orders of magnitude faster. For locally estimating the required OPLS-AA force field parameters with the LigParGen and BOSS software packages, a user-friendly graphical user interface for the Windows operating system is provided. Scientific contribution Rapid calculation of mutual intermolecular energies for a set of monomer molecules based on the widely used OPLS-AA force field enables a considerable expansion of this type of calculation for practical purposes. The performance improvement can be used to achieve significant improvements of interaction energy averages as well as considerable expansions in the size of the monomer molecule set.
Mirco Daniel, Hannah Kullik, Martin Urban et al.· Journal of Cheminformatics· 0 citations
Accurate solvation free energies from molecular dynamics simulations require efficient sampling of coupled slow variables, including solvent coordinates, solute conformational modes, and the alchemical coordinate $\lambda$. Here, we develop a $\lambda$-dynamics framework that combines mass scaling, on-the-fly probability enhanced sampling (OPES), and driven adiabatic free energy dynamics (d-AFED) to address these sampling challenges within a unified protocol. For rigid organic solutes, Hamiltonian replica exchange with mass scaling is first used to quantify the effect of octanol solvent relaxation. Reducing all octanol atomic masses by a factor of ten accelerates convergence by more than fivefold while preserving equilibrium solvation free energies. These calculations then provide reference benchmarks for $\lambda$-OPES, a dual-bias $\lambda$-dynamics strategy that combines the"standard"and"explore"variants of OPES to promote transitions along the alchemical coordinate. This approach reaches convergence on timescales comparable to replica exchange, but without predefined $\lambda$ windows or multiple parallel simulations. For flexible $N$-acetyl amino-acid amide solutes, $\lambda$-OPES is coupled with d-AFED on selected backbone and side-chain dihedrals to enable simultaneous alchemical and conformational enhanced sampling. This combined strategy improves agreement with experimental octanol-water partition coefficients and reduces the mean absolute error from 0.75 log units with $\lambda$-OPES alone to 0.30 log units with $\lambda$-OPES-d-AFED. Overall, this work establishes an integrated enhanced sampling protocol for solvation free energy calculations across rigid organic solutes and flexible peptide-like solutes, and provides a foundation for the application of alchemical free energy methods to larger and more conformationally complex systems.
Gabriela B. Correa, C. Abreu, Nishanth N Nair et al.· 0 citations
A novel X10 benchmark set is introduced to enable an assessment of the computational performance of atomistic simulations of enthalpies of fusion for molecular materials. The fusion enthalpy, i.e. the enthalpy of melting, represents a fundamental descriptor of the solid-liquid equilibrium, and as such, the ability to predict this property is highly valuable across various fields of material design. Computational accuracy is tested for all-atom molecular-dynamics simulations, relying either on a classical generic non-polarizable force-field model (MD), or on a selected density-functional-theory (DFT) treatment of the electronic degrees of freedom in ab initio molecular dynamics (AIMD). Performance of these MD and AIMD methods is critically assessed against reference experimental data and it is evaluated in terms of the fusion enthalpies and related structural descriptors, such as bulk phase densities. A detailed interpretation of the predicted fusion enthalpies in terms of important cohesive non-covalent interactions, such as hydrogen bonding and dispersion forces, and variations of their intensity upon melting is presented. A special emphasis is laid on investigations of the finite-size artifacts that are necessarily at play in costly AIMD simulations that are feasible only for small molecular ensembles. The presented results indicate that the fusion enthalpies for neutral-molecular materials can be typically predicted within roughly 2 kJ mol-1 from the experiment with the PBE-D3(BJ)/GTH based AIMD model, yielding a somewhat higher accuracy on average than the classical force-field based simulations. This finding is important as similar DFT theories are commonly used nowadays as a source of training data for development of machine-learning interatomic potentials.
Jan Ludík, Ctirad Červinka· Physical Chemistry, Chemical...· 0 citations
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