Protein-protein binding pathways and calculations of rate constants using fully-continuous, explicit-solvent...

Area of Science:

• Biophysics
• Computational Biology
• Molecular Dynamics

Background:

• Characterizing protein-protein binding at atomic resolution is a major biophysics challenge.
• Transient intermediate states in binding are difficult to capture experimentally.
• Atomistic simulations offer a way to visualize these dynamic processes.

Purpose of the Study:

• To simulate and characterize protein-protein binding pathways at atomic resolution.
• To identify rate-limiting steps and key molecular interactions during binding.
• To assess the feasibility of atomistic simulations for studying binding dynamics.

Main Methods:

• Weighted ensemble path sampling strategy was employed.
• Orchestrated atomistic simulations of barnase-barstar binding.
• Generated 203 continuous and independent binding pathways.

Main Results:

• Identified a funnel-like free energy landscape for binding.
• Encounter complex formation was found to be rate-limiting.
• Protein rotation via electrostatic steering and subsequent rolling facilitated productive collisions (∼11% efficiency).
• Residue R59 on barnase is critical for binding kinetics.
• Protein desolvation occurs late in the binding process.

Conclusions:

• Atomistic simulations are now practical for studying protein-protein binding.
• The study provides atomic-level insights into barnase-barstar interactions.
• Key intermediates and conformational changes during binding were elucidated.