Enzyme-inhibitor association thermodynamics: explicit and continuum solvent studies

Area of Science:

• Biochemistry
• Computational Chemistry
• Molecular Dynamics

Background:

• Studying biochemical association reactions requires efficient sampling of molecular configurations and solvent interactions.
• Disconnected solvent cavities in binding sites pose sampling challenges for explicit solvent simulations.

Purpose of the Study:

• To calculate the association free energy profile between trypsin and benzamidine using the grand canonical Monte Carlo (GCMC) method.
• To compare GCMC results with a continuum solvent model and validate simulation accuracy against crystal structures.

Main Methods:

• Grand Canonical Monte Carlo (GCMC) simulations to determine the potential of mean force.
• Continuum solvent model using the Poisson equation for comparison.
• Analysis of solvation structure and comparison with experimental crystal structures.

Main Results:

• The GCMC method successfully calculated the association free energy profile between trypsin and benzamidine.
• Continuum solvent model results closely matched explicit solvent simulation findings.
• Simulated solvation structures, including bridging waters, agreed well with crystal structure data.

Conclusions:

• The grand canonical ensemble is a viable method for overcoming sampling limitations in explicit solvent simulations.
• Continuum solvent models offer a surprisingly accurate and efficient alternative for calculating binding free energies.
• The simulations accurately predict solvation structures, supporting their reliability for studying molecular recognition.