Jul 2026· Journal of Chemical Theory and Computation· 0 citations· 51 references
Medicine
Abstract
Solvent can reorganize reaction paths and barriers, but bringing those effects into mechanistic calculations remains expensive, because every image in a solvated climbing-image nudged elastic band search requires a new self-consistent reaction-field calculation. Here, we present a high-fidelity surrogate framework that keeps a preconstructed nonsolvated reaction valley as the backbone and models only the geometry-dependent solvent contribution needed to transform it into the solution-phase potential of mean force, i.e., the solvent-shaped free-energy surface. Using uncertainty-selected evaluations with the plane-wave implicit solvation model based on electron density (PW-SMD), the method optimizes solvated reaction paths on the fly and recovers 300 K free-energy profiles from local surrogate Hessians. For 16 small-molecule reactions in water and 17 Cu(111) interfacial reactions, the framework reduces the average number of solvent-response calculations from 826.3 to 67.3 and from 1231.9 to 51.5, respectively, while maintaining small-molecule barrier differences of only 0.04 eV on average and an interfacial reaction barrier agreement within a few hundredths of an eV for most reactions. The surrogate also reproduces representative room-temperature activation and reaction free energies. These results show that solvent-induced reshaping of reaction pathways can be captured accurately from a sparse, strategically chosen set of solution-phase calculations, turning solvated reaction-path and free-energy calculations into a practical tool for molecular and interfacial mechanistic studies.
Accurate modeling of nonbonded interactions remains challenging because conventional force fields often provide inadequate descriptions of polarization and charge transfer. Here, we introduce a polarizable split-charge equilibration (PSQ) framework that combines localized charge flow with dipolar polarization, thereby mitigating the unphysical long-range charge delocalization associated with polarizable charge-equilibration models. To enable practical large-scale simulations, we develop an efficient PSQ implementation through algorithmic optimization and parallelization, achieving performance comparable to conventional approaches despite the model’s greater formal complexity. We combine PSQ with the universal nonbond potential for van der Waals interactions and an explicit four-body hydrogen-bond term to form the PUxH framework. PUxH achieves near-chemical accuracy in predicting small-molecular pair interactions and accurately reproduces the bulk properties of water, ammonia, and benzene. Overall, PUxH provides a transferable, physically grounded, and computationally efficient framework for modeling nonbonded interactions in molecular and condensed-phase systems.
Taehwan Jang, Minho M. Kim, Hoon Ryu et al.· Journal of Physical Chemistr...· 0 citations
In quantum chemical descriptions of solutions, solvents are treated either implicitly, accounting only for bulk properties, or explicitly by including solvent molecules in the calculations. Although explicit treatments are more accurate, they are often computationally prohibitive. As a cost-effective alternative, microsolvation models have emerged that include only a limited number of solvent molecules to capture the most relevant solute–solvent interactions. However, determining their optimal number, positions, and orientations remains a challenge. Existing approaches typically either build up solvent clusters in a stepwise, order-dependent manner or select solvent molecules based on geometric criteria without directly quantifying interaction strength. Here, we introduce the Free Energy Based Identification of Solvation Sites (FEBISS) 2, a revised microsolvation protocol based on Grid Inhomogeneous Solvation Theory (GIST) applied to molecular dynamics trajectories. The method identifies thermodynamically favorable solvation sites from Free Energy contributions. It automatically places, orients, and ranks solvent molecules by interaction strength, using a statistically averaged, order-independent orientation procedure that is applicable to arbitrary rigid solvents rather than water alone. This approach provides a physically grounded criterion for selecting the number of solvent molecules in microsolvated clusters. We demonstrate the applicability of the approach across a range of systems, from small organic molecules to transition-metal catalysts, and for various solvents. We show that explicit microsolvation affects the electronic structure even in systems traditionally considered weakly solvent-sensitive, highlighting FEBISS 2 as a practical methodology to set up physically meaningful microsolvation clusters for quantum chemical studies.
Unknown authors· Journal of Chemical Theory a...· 0 citations
We propose an improved model, termed the gradient-corrected PCM (GCPCM), for improving the energy accuracy of the polarizable continuum model (PCM). Our previous study revealed deficiencies of PCM in describing the reaction field, i.e., the electrostatic potential generated by the solvent. These deficiencies can be partially alleviated by introducing an empirical correction to the solvent charges. As a result, solute-solvent interactions are improved at the self-consistent field level, leading to enhanced energy accuracy. The performance of GCPCM was evaluated through single-point calculations and geometry optimizations of phenol and phenolate, calculations of the free energy profile for proton transfer in glycine, and analysis of solvent responses of the HOMO and LUMO orbital energies of Brooker's merocyanine. The results demonstrate that the characteristic destabilization of charged solutes observed in conventional PCM is effectively resolved. Furthermore, despite having a computational cost comparable to that of PCM, GCPCM shows the potential to achieve an energy accuracy similar to that of 3D-RISM-SCF. The development of GCPCM enables more convenient and accurate treatment of solvation effects, which is expected to allow researchers to focus on other important challenges, such as the accurate description of electronic states.
Y. Kanamaru, Norio Yoshida, Toru Matsui· Journal of Chemical Theory a...· 0 citations
Solvent effects permeate essentially all solution‐phase chemistry. Yet, a unified and generally predictive description remains challenging because solvent effects span multiple length and time scales: bulk dielectric screening and viscosity capture only part of the physics, while first‐shell coordination, ion pairing, hydrophobic aggregation, and heterogeneous structural fluctuations can be decisive near the reaction coordinate; moreover, when solvent relaxation occurs on time scales comparable to chemical events, nonequilibrium solvation and memory effects may invalidate static free energy corrections. This review outlines a practical trajectory from early phenomenology to modern computation and, more recently, data‐driven decision making. We first revisit the conceptual roots of solvent effects and the rise of empirical solvent scales that compress complex microscopic behavior into usable descriptors. We then summarize the logic of implicit, explicit, and hybrid solvent models in contemporary computational chemistry, emphasizing their assumptions, cost‐accuracy trade‐offs, and applicability. Finally, we discuss data standardization and benchmarking for solvation modeling, learning‐based prediction of properties and solvation free energies, machine‐learned potentials that enable scalable explicit solvent simulations, and emerging workflows for solvent/condition recommendation and closed‐loop optimization.
Unknown authors· Chinese journal of chemistry· 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
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