Discovering cryptic pocket opening and binding of a stimulant derivative in a vestibular site of the 5-HT_3A receptor.

ABSTRACT: A diverse set of modulators, including stimulants and anesthetics, regulates ion channel function in our nervous system. However, structures of ligand-bound complexes can be difficult to capture by experimental methods, particularly when binding is dynamic. Here, we used computational methods and electrophysiology to identify a possible bound state of a modulatory stimulant derivative in a cryptic vestibular pocket of a mammalian serotonin-3 receptor. We first applied a molecular dynamics simulation-based goal-oriented adaptive sampling method to identify possible open-pocket conformations, followed by Boltzmann docking that combines traditional docking with Markov state modeling. Clustering and analysis of stability and accessibility of docked poses supported a preferred binding site; we

SUBMITTER: Haloi N 

PROVIDER: S-EPMC11988449 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature