Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

Abstract

With a view to improving the consistency of free energy perturbation calculations in Monte Carlo simulations of protein–ligand complexes, we have implemented the replica exchange with solute tempering (REST) method in the MCPRO software. By augmenting the standard REST approach with regular attempted jumps in selected dihedral angles, our combined method facilitates sampling of ligand binding modes that are separated by high free energy barriers and ensures that computed free energy changes are considerably less dependent on the starting conditions and the chosen mutation pathway than those calculated with standard Monte Carlo sampling. We have applied the enhanced sampling method to the calculation of the activities of seven non-nucleoside inhibitors of HIV-1 reverse transcriptase, and its Tyr181Cys variant, and have shown that a range of binding orientations is possible depending on the nature of the ligand and the presence of mutations at the binding site.

Accurate and Reliable Prediction of Relative Ligand Binding Potency in Prospective Drug Discovery by Way of a Modern Free-Energy Calculation Protocol and Force Field

“…1. The performance of the non-bonded interaction model has been initially evaluated in the prediction of aqueous solvation free energies, the results of which are reported in a prior publication 32 and summarized in 39 The REST methodology thus enables problematic torsional barriers, which can limit ergodicity, to be surmounted in a routine fashion. 8 A crucial aspect of the use of FEP/REST in practical calculations is the selection of the REST region.…”

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

“…As with any computational approach, accuracy in predicting experiment requires a synergy of sufficient conformational sampling with an accurate molecular mechanics potential energy function describing the intermolecular interactions 2. Many sampling issues have been dealt with using intensive enhanced sampling methods coupled to molecular dynamics (MD)3, 4, 5 or Monte Carlo methods 6, 7. However, the issues associated with potential energy function or force field accuracy are substantially more problematic and remain a major challenge in force field development and molecular recognition applications 8, 9…”

Molecular dynamics and Monte Carlo simulations for protein–ligand binding and inhibitor design

“…The predictive power of FEP relies on the assumption of ergodicity, that is, that in effect all relevant geometries of the protein–ligand complex are being sampled with the correct Boltzmann weight. Numerous examples of quasi-ergodic sampling have been reported in both the MD and MC literature, whereby the protein and/or the ligand are trapped for long times in local free-energy minima [6-8]. There are, however, a wide range of enhanced sampling methods available, usually based on tempering the system or modifying the underlying potential energy surface, which can circumvent this problem without significantly affecting the computational cost [9].…”

“…This allows the heating of local regions of the system, thus substantially improving traversal of the free energy surface while sampling rigorously from the Boltzmann ensemble. The REST algorithm has been shown to improve agreement with experiment in typical medicinal chemistry projects [8,22]. Both codes use OPLS force fields [23,24], though there are differences in the parameters and the assignment of partial charges [11,12,25,26].…”

“…The application of MCPRO with REST to the optimization of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) has previously been described [8]. This class of molecules is an important component of anti-HIV treatment; however, patients who begin NNRTI treatment often develop the Tyr181Cys (Y181C) mutation, which renders many agents inactive.…”