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