Multiple Ligand Unbinding Pathways and Ligand-Induced Destabilization Revealed by WExplore

Area of Science:

• Computational chemistry
• Biophysics
• Molecular dynamics

Background:

• Understanding ligand-protein interactions is crucial for drug discovery.
• Simulating rare events like ligand unbinding remains computationally challenging.

Purpose of the Study:

• To simulate and analyze full ligand exit pathways for the trypsin-benzamidine system.
• To investigate the properties of ligand binding and identify key binding poses.

Main Methods:

• Utilized the WExplore sampling technique to simulate millisecond-scale unbinding events.
• Employed a weighted ensemble method with on-the-fly region division, cloning, and merging.
• Visualized pathways using conformation space networks.

Main Results:

• Achieved a ligand exit rate of 180 μs, close to experimental values.
• Identified three distinct ligand exit channels, two involving rare loop motions.
• Observed direct stabilization and indirect destabilization effects of ligand binding.

Conclusions:

• WExplore effectively simulates rare unbinding events and provides broad pathway sampling.
• Crystallographic poses are characterized by strong stabilization and minimal destabilization of protein interactions.