Kinetics of desolvation-mediated protein-protein binding.

Area of Science:

• Biophysics
• Computational Chemistry
• Biochemistry

Background:

• Protein-protein interactions are crucial for biological processes.
• Understanding binding kinetics is key to drug design and protein engineering.
• The role of desolvation in protein binding kinetics is not fully understood.

Purpose of the Study:

• To investigate the role of desolvation in protein binding kinetics.
• To quantify the contribution of desolvation to binding free energy and association rates.
• To explore the mechanisms by which desolvation influences protein complex formation.

Main Methods:

• Brownian dynamics simulations were employed.
• A short-range atomic contact potential was used to model partial desolvation.
• Simulations were performed on protein complexes with weak electrostatic interactions, including alpha-chymotrypsin, human leukocyte elastase, and turkey ovomucoid third domain.

Main Results:

• Partial desolvation significantly increases the diffusion-limited rate for protein complex formation.
• Rate enhancement is attributed to weakly specific pathways leading to a low free-energy attractor (precursor state).
• Calculated forward rate constants for specific protein complexes align with experimental data, supporting the existence of diffusion-accessible precursor states.
• Desolvation restricts nonspecific association times, preventing protein aggregation.

Conclusions:

• Desolvation is a major contributor to binding free energy and substantially increases association rates.
• Protein complex formation involves well-defined precursor states preceding the final bound conformation.
• Desolvation plays a critical role in preventing nonspecific protein aggregation.
• While desolvation enhances rates, electrostatically assisted binding remains significantly faster.