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Preprint Aug 2026

Evaluating Electrostatic Embedding MLIP/MM for Relative Binding Free Energy Calculations

Electrostatic embedding improved every accuracy and correlation metric for TYK2 but performed comparably to the classical and mechanical-embedding baselines for CDK2, thrombin, p38 and JNK1, and standard single-molecule energy and charge benchmarks were not good predictors of this target-dependent outcome.

Stephen E. Farr, G. D. Fabritiis · 0 citations
Preprint Aug 2026

On calculating polar solvation energy of nonrigid proteins in the Poisson-Boltzmann theory

The Poisson-Boltzmann (PB) theory is a cornerstone of implicit solvent models for electrostatic analysis, and has found a great success in various biomolecular applications. However, in calculating polar solvation energy, one should consider that the structure of the protein changes upon transition from vacuum to water phases. To address this, here we report for the first time a generalized PB framework capable of accommodating nonrigid conformational changes without suffering from self-energy artifacts. For regularized PB models, in which the charge singularities are captured by the Green's functions, self-energies in the water and vacuum states will be analytically canceled. For non-regularized PB solvers, such as APBS and DelPhi, a simple thermodynamic cycle is proposed for nonrigid proteins by adding a Coulombic correction in vacuum. 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
Open access Aug 2026

Fast intermolecular interaction energy calculation with the OPLS-AA force field

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. · 0 citations
Jul 2026

Charged Systems in Absolute Binding Free Energy Calculations: An Analytical Electrostatic Approach.

Alchemical free energy perturbation (FEP) is one of the most rigorous methods for predicting protein-ligand binding affinities, yet charged-ligand calculations suffer from finite-size electrostatic artifacts introduced by periodic boundary conditions, which can bias results by several kcal·mol-1. Existing approaches each have limitations: finite-size correction methods rely on approximate dielectric models and Poisson-Boltzmann (PB) calculations, while alchemical co-ion methods introduce alchemically transformed particles, causing spurious interactions and sampling difficulties. Here we present Electrostatic Interaction Decoupling (EID), a postprocessing approach that combines an exact algebraic isolation of the ligand-environment linear electrostatic interaction under the neutral-environment condition with an analytical correction for the residual periodic-boundary offset. By separating the physical ligand-environment interaction from artifact-contaminated terms, EID corrects charge-changing FEP results without PB/continuum-electrostatics calculations or alchemically transformed particles. In benchmarks across four charged protein-ligand systems, EID achieved improved predictive accuracy and more consistent cross-system performance than both comparison methods. Because EID operates as a postprocessing step requiring no additional simulations or PB calculations, it provides a rigorous, immediately deployable solution for charge-changing free energy calculations.

Runduo Liu, Wanyi Huang, Yufen Yao et al. · 0 citations
Aug 2026

Accurate Atomic Decomposition Method in 3D-RISM Theory via Multi-Input Linear Correction: Application to the Protein Hydrophobic Core

Solvation free energy (SFE) is a fundamental thermodynamic quantity governing biomolecular processes in solution. Although the atomic decomposition method derived from the Kirkwood charging formula enables site-resolved evaluation of SFE contributions, its application within the three-dimensional reference interaction site model (3D-RISM) theory suffers from systematic overestimation relative to benchmark values. Here, we developed the Multi-Input Linear Correction for Atomic Decomposition (MILC-AD) framework by extending the original MILC approach to the atomic decomposition scheme within 3D-RISM theory. Unlike the original MILC framework, which relies on the nondecomposable partial molar volume (PMV), the proposed method uses atomically decomposable solute–solvent interaction energies as descriptors. Validated against 628 molecules from the benchmark FreeSolv database, the framework achieves a mean absolute deviation (MAD) of 0.57 kcal/mol relative to the Bennett acceptance ratio (BAR) calculations using ensemble-averaged predictions over ten conformations per molecule. As a representative application, the method is applied to the 36-residue villin headpiece subdomain HP36, revealing the site-resolved balance between intramolecular packing, SFE, and solvation entropy underlying the cooperative assembly of its hydrophobic core. These results demonstrate the potential of the MILC-AD framework as a practical tool for quantitative, site-resolved thermodynamic analyses of complex biomacromolecular systems.

Yutaka Maruyama, Norio Yoshida · 0 citations
Jul 2026

Free Energies of Solvation in Cyclohexane and Water: United-Atom vs All-Atom.

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.

W. Jorgensen, J. Tirado-Rives · 0 citations