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.
Simulating systems with rugged free-energy landscapes remains a central challenge in computational physics and chemistry. We introduce hyperspatial replica exchange (HS-REX), an enhanced sampling method in which the physical system is artificially extended by additional spatial dimensions. In higher dimensions, free-energy barriers can be circumvented through paths that are geometrically inaccessible in the original space. Restricting the penalty to only solute atoms dramatically reduces the number of replicas required for solvated systems compared to standard temperature replica exchange, a feature especially relevant for biological applications. As proof of concept, we demonstrate the method on a double-well model system and on alanine dipeptide in explicit water as benchmark system. In the latter case, HS-REX achieves enhanced conformational sampling of not only the slow backbone dihedral angles, but also both chiral configurations of the molecule, which are sterically inaccessible to standard sampling in three dimensions. This demonstrates enhanced ergodic sampling over conventional temperature replica exchange.
Henrik Christiansen, Matheus Ferraz, Takashi Maruyama et al.· 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
Alchemical free energy (AFE) calculations are a useful tool in computational drug discovery. However, they typically involve relatively short (<10 ns) simulations, meaning that the initial coordinates and, more generally, the setup of the system have a significant effect on the obtained free energy values. To remedy this, we recently developed a fully adaptive version of the simulated tempering algorithm (FAST) and applied it in the context of sampling. In this work, we extend FAST to AFE calculations with and without enhanced sampling of a particular degree of freedom of interest (FAST/MBAR). We show that enhanced sampling significantly increases the mobility of the targeted degree of freedom at the cost of reduced sampling efficiency over λ space. On the other hand, the free energy calculations without explicit targeting of certain degrees of freedom retain initial-coordinate bias over longer time scales. Despite this, both protocols readily explore nanosecond-time-scale events, such as torsional rotation, due to the single-trajectory nature of FAST, making them less sensitive to the system preparation. It is shown that the robust automated nature of FAST/MBAR makes it a competitive alternative to conventional AFE methods.
Miroslav Suruzhon, Justina Ratkeviciute, Khaled Abdel-Maksoud et al.· Journal of Chemical Theory a...· 0 citations
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· Journal of Chemical Theory a...· 0 citations
This work employs a dual-coordinate approach where both solutes are explicitly present but do not interact with one another, and utilizes a harmonic ″anchor″ restraint to a central atom on each molecule to enforce spatial overlap without modifying the internal intramolecular dynamics of either solute.
Anna Katharina Picha, S. Boresch· Journal of Chemical Theory a...· 1 citation
It is valuable to calculate alchemical free energy changes in drug discovery and development. Thermodynamics Integration (TI) has been widely used in computational chemistry for estimating free energy changes with alchemical transformations. However, TI based on usually short Molecular Dynamics (MD) simulations often suffers from insufficient conformational sampling. Here, we have integrated Gaussian accelerated MD and TI (GaMD-TI) to enhance the conformational sampling and improve accuracy of free energy calculations. GaMD-TI has been demonstrated in model systems of alchemical changes in the Valine dipeptide and mutation cycle of the Alanine ↔ Valine ↔ Isoleucine (AVI) residues. Simulations showed that when GaMD boost potentials followed near-Gaussian distribution, the free energy change could be reweighted accurately through generalized cumulant expansion to the second order. The total free energy change often exhibited faster convergence using Selective GaMD (SGaMD) than using conventional MD (cMD). Accuracy of the free energy estimates from SGaMD-TI simulations was similar to or higher than those from cMD-TI simulations, although the differences were subtle for these small model systems. Meanwhile, dihedral angles in the model systems underwent significantly more frequent conformational transitions in SGaMD than in cMD, indicating improved sampling. Future studies are planned on larger systems with more complicated alchemical changes, such as ligand binding to proteins/nucleic acids and mutations at biomolecular binding interfaces. GaMD-TI should be broadly applicable to alchemical free energy calculations and therapeutic design. Significance Statement It is valuable to calculate alchemical free energy changes in drug design. We have integrated Gaussian accelerated Molecular Dynamics (GaMD) and Thermodynamics Integration (TI) for more efficient free energy calculations. Results that when GaMD boost potentials followed near-Gaussian distribution, the free energy change were reweighted accurately through generalized cumulant expansion to the second order. The total free energy change often exhibited faster convergence using Selective GaMD than using conventional MD, with significantly enhanced conformational sampling. Future studies are planned on larger systems with more complicated alchemical changes. GaMD-TI should be broadly applicable to alchemical free energy calculations.
Unknown authors· bioRxiv· 0 citations
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