Protein-Ligand Dissociation Rate Constant from All-Atom Simulation

Area of Science:

• Biophysics
• Computational Chemistry
• Pharmacology

Background:

• Understanding ligand-protein interactions is crucial for drug development.
• Catalase is a vital enzyme, and its interaction with isoniazid, an antituberculosis drug, requires detailed investigation.
• Accurate prediction of dissociation times is essential for characterizing drug efficacy and binding kinetics.

Purpose of the Study:

• To investigate the dissociation of isoniazid from catalase using advanced simulation techniques.
• To develop and validate a novel method for extrapolating dissociation times to zero-force conditions.
• To compare simulation-derived dissociation times with experimental values.

Main Methods:

• All-atom molecular dynamics (MD) simulations were employed.
• Accelerated MD simulations, specifically τ-RAMD, were utilized to enhance ligand dissociation.
• A new extrapolation approach based on a universal exponential force dependence was developed.

Main Results:

• The study successfully calculated the dissociation time of isoniazid from catalase as 36.1 seconds.
• The extrapolated value quantitatively matched the experimental dissociation time of 50 ± 8 seconds.
• The novel extrapolation method proved effective over nine orders of magnitude in time.

Conclusions:

• The developed τ-RAMD simulation and extrapolation methodology provides a reliable approach for predicting ligand-protein dissociation times.
• This method offers a powerful tool for quantitatively assessing drug-target interactions.
• The findings contribute to a deeper understanding of isoniazid's mechanism of action and binding kinetics with catalase.