Enhanced Sampling Simulations of Ligand Unbinding Kinetics Controlled by Protein Conformational Changes

Area of Science:

• Computational chemistry and biophysics
• Molecular dynamics simulations
• Pharmacology

Background:

• Protein-ligand unbinding kinetics are vital for designing specific and safe ligands.
• Enhanced sampling techniques aid atomistic studies of unbinding.
• Coupling of ligand unbinding to protein conformational changes poses a significant sampling challenge.

Purpose of the Study:

• To investigate the unbinding mechanism of [18F]ASEM from the α7-nicotinic acetylcholine receptor.
• To demonstrate the combined utility of potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) for studying complex unbinding pathways.
• To elucidate the role of protein conformational changes in ligand dissociation.

Main Methods:

• Utilized potential-scaled molecular dynamics (sMD) to explore initial ligand egress pathways.
• Employed infrequent metadynamics (InMetaD) with protein conformational changes (loop C) as collective variables.
• Simulated the unbinding of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluorodibenzo[b,d]thiophene 5,5-dioxide ([18F]ASEM) from a chimera α7-nicotinic acetylcholine receptor structure.

Main Results:

• sMD simulations revealed that the loop C conformational change from 'close' to 'open' is critical for [18F]ASEM unbinding.
• InMetaD simulations successfully captured key intermediate states during the unbinding process.
• The study clarified the detailed unbinding mechanism of [18F]ASEM, influenced by receptor dynamics.

Conclusions:

• The combination of sMD and InMetaD is an effective strategy for studying protein-ligand unbinding mechanisms.
• Protein conformational dynamics significantly influence ligand dissociation pathways.
• This approach enhances the understanding of ligand behavior in complex biological systems.