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
High-fidelity quantum chemical (QM) data sets that jointly resolve reaction thermochemistry, kinetics, and solvation at scale remain scarce, especially for radical chemistry. We introduce QuantumPioneer, an open-access reaction-centered QM database and workflow for small organic molecules, focused on peroxyl-mediated hydrogen atom transfer (HAT) and the corresponding homolytic bond dissociation reactions. QuantumPioneer contains 348,258 species (2–21 heavy atoms), 167,237 validated HAT transition states (TS) with corresponding reaction energies and homolytic bond dissociation energies (BDEs), and over 100 million COSMO-RS solvation free energies(ΔGsolv*) and enthalpies (ΔHsolv*) across 295 solvents. The workflow uses ωB97X-D/def2-SVP geometries, DLPNO–CCSD(T)-F12d/cc-pVTZ-F12 single-point energies, empirical thermochemical corrections, transition-state theory, and COSMO-RS BP-TZVPD-FINE solvation in a single high-throughput pipeline. Our benchmarks show reliable accuracy, with mean absolute errors (MAEs) compared to experimental and high-level QM reference data of 0.82 kcal/mol for gas-phase enthalpies of formation, 1.60 kcal/mol for C–H BDEs, 1.45 kcal/mol for HAT barriers, and 0.57 kcal/mol for ΔGsolv* values. We demonstrate two predictive applications. First, we show that combining BDE and HAT-barrier models identifies experimentally observed oxidative degradation sites in drug-like molecules with a 91% top-5 hit rate and 82% site-level recall. Second, we show that a QM-parametrized Abraham model enables rapid solvation energy estimates at near-COSMO-RS accuracy within its training domain, reproducing computed ΔGsolv* and ΔHsolv* values with MAEs of 0.16 and 0.18 kcal/mol, respectively, though performance on experimental ΔGsolv*values for unseen solutes was worse, with an MAE of 1.32 kcal/mol. This work provides a scalable template for other reaction families, unifying equilibrium species, validated TS, thermochemistry, kinetics, and solvation into one workflow.
Haoyang Wu, Jonathan W. Zheng, Hao‐Wei Pang et al.· Journal of the American Chem...· 1 citation
This work proposes pretraining on low-noise, calculable molecular descriptors via supervised learning to obtain rich, highly transferable molecular representations and demonstrates this strategy with CheMeleon, a O(10M) parameter foundation model that enables directed message-passing neural networks to finally exceed the performance of classical methods in the low-data regime.
Jackson W. Burns, Akshat Shirish Zalte, C. Abreu et al.· Journal of Chemical Informat...· 0 citations