Dealing with induced fit, conformational selection and secondary poses in molecular dynamics simulations for reliable free energy predictions

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 induced fit (phenyl-based host) and conformation selection (naphtyl-based host), and of the ODR-BRD4(I) drug-receptor system where the ODR ligand can assume two main poses. For the optimization of the HREM simulation, we have proposed an on-the-fly iterative scheme for equalizing the acceptance ratio along the replica progression at constant replica number. We have found that while short MD replicates are able to sample as effectively as HREM the diverse conformational states in the phenyl-based host and in the ODR-BRD4(I) complex, in the naphtyl-based macrocycle, characterized by long-lived meta-stable states, HREM is the only viable alternative for a reliable canonical sampling of the rugged conformational landscape. Implications of these results for free energy calculation of binding free energy in drug-receptor systems are highlighted.