Path-Based Nonequilibrium Binding Free Energy Estimation, from Protein-Ligand to RNA-Ligand Binding.

ABSTRACT: In this study, we addressed the challenge of estimating binding free energies in complex biological systems of pharmaceutical relevance, including both protein-ligand and RNA-ligand complexes. As case studies, we examined the intricate binding of the drug Gleevec to Abl-tyrosine kinase and two ligands binding to the preQ1 RNA riboswitch. By refining our approach based on nonequilibrium steered molecular dynamics simulations and path-based collective variables, we tackled the specific difficulties posed by these systems. In particular, the Abl-Gleevec complex is characterized by significant system size and extensive conformational rearrangements of the protein, whereas the systems involving RNA are characterized by marked conformational flexibility. For the Abl-Gleevec system, our method pr

SUBMITTER: Serra E 

PROVIDER: S-EPMC12199290 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature