Can MM/GBSA calculations be sped up by system truncation?

Area of Science:

• Computational chemistry
• Molecular modeling
• Biophysics

Background:

• Accurate calculation of protein-ligand binding free energy is crucial for drug discovery.
• The MM/GBSA method is a popular approach for such calculations.
• Reducing computational cost is essential for high-throughput screening.

Purpose of the Study:

• To investigate the feasibility of accelerating MM/GBSA calculations by reducing the number of atoms included.
• To determine the optimal system size for accurate binding free energy estimations.
• To assess the impact of system truncation on simulation accuracy.

Main Methods:

• Molecular mechanics combined with generalized Born and surface area solvation (MM/GBSA) approach.
• Molecular dynamics (MD) simulations were performed on protein-ligand systems.
• System truncation was evaluated at different stages: before and after MD simulations.
• Binding free energies were calculated for truncated and full systems.

Main Results:

• Truncating the protein before MD simulations led to significant changes in binding energy (e.g., 4 kJ/mol at 19 Å for phenol derivatives).
• Errors were reduced when no atoms were fixed during simulations (avg. 2 kJ/mol at 19 Å).
• Truncating snapshots after MD simulations allowed omitting atoms >8.5 Å from the ligand with minimal energy change (avg. 1 kJ/mol).

Conclusions:

• Truncating protein systems *after* MD simulations is a viable strategy to reduce computational cost for MM/GBSA calculations.
• This approach is particularly relevant for more computationally demanding methods like quantum mechanics.
• Careful consideration of truncation strategy is necessary to maintain accuracy in binding free energy calculations.