Rapid rescoring and refinement of ligand-receptor complexes using REMD with a MC pose reservoir

Virtual screening (VS) involves generation of poses for a library of ligands, and ranking using simplified energy functions and limited flexibility. Top scored poses are used to rank and prioritize ligands. Here we adapt the reservoir replica exchange molecular dynamics (res-REMD) method to re-rank poses generated through VS. REMD simulations are carried out, but with occasional Monte Carlo jumps to alternate VS-generated poses using a Metropolis criterion. The simulations converge within 10 ns for all systems, generating populations of alternate poses in the context of fully flexible ligand and protein side chains. The protocol is applied to four model protein-ligand complexes, where DOCK resulted in two successes and two scoring failures. In all four systems, the most populated cluster from the final ensemble exhibits high similarity to the crystallographic pose, with ligand RMSD values under 2.0 Å. Both DOCK failures were rescued. For one DOCK success, the protocol identified the correct pose, but also sampled an alternate pose at equal probability. Opportunities for future improvement and extension are discussed.