Dealing with Induced Fit, Conformational Selection, and Secondary Poses in Molecular Dynamics Simulations for Reliable Free Energy Predictions

Abstract

In this study, we have tested the performance of standard molecular dynamics (MD) simulations, replicates of shorter standard MD simulations, and Hamiltonian Replica Exchange (HREM) simulations for the sampling of two macrocyclic hosts for guest delivery, characterized by induced fit (phenyl-based host) and conformation selection (naphthyl-based host) and of the ODR-BRD4(I) drug-receptor system where the ligand can assume two main poses. For the optimization of the HREM simulation, we have proposed and tested an on-the-fly iterative scheme for equalizing the acceptance ratio along the replica progression at a constant replica number resulting in a moderate impact of the sampling efficiency. Concerning standard MD, we have found that, while splitting the total allocated simulation time in short MD replicates can reproduce the sampling efficiency of HREM in the phenyl-based host and in the ODR-BRD4(I) complex, in the naphthyl-based macrocycle, characterized by long-lived metastable states, enhanced sampling techniques are the only viable alternative for a reliable canonical sampling of the rugged conformational landscape.

Identification of Potential Inhibitors of the SARS‐CoV‐2 NSP13 Helicase via Structure‐Based Ligand Design, Molecular Docking and Nonequilibrium Alchemical Simulations

“…More specifically, in the first step we collected hundreds of uncorrelated equilibrium configurations of the solvated complex by running replicates of MD simulations for a total time of '0.2 microseconds for each of the eight selected ligandreceptor systems. Independent MD replicates have been shown in several instances [36,39] to provide a sampling as accurate as that of the expensive Replica Exchange Method (HREM). [39,40] For the decoupled ligand, canonical sampling is efficiently obtained performing an HREM simulation of the gas-phase solute molecule alone, combined with equilibrium configurations of the solvent.…”

“…Independent MD replicates have been shown in several instances [36,39] to provide a sampling as accurate as that of the expensive Replica Exchange Method (HREM). [39,40] For the decoupled ligand, canonical sampling is efficiently obtained performing an HREM simulation of the gas-phase solute molecule alone, combined with equilibrium configurations of the solvent. In the second alchemical step, two independent parallel jobs, corresponding to NE fast decoupling trajectories of the initially equilibrated ligand in the bound state, and to the NE recoupling trajectories of the initially equilibrated ligand, concur to the determination of the standard dissociation free energy as a functional, E, of the convolution of the bound-state and unbound state alchemical work distributions, i. e.:…”