Generalizing the Discrete Gibbs Sampler-Based λ-Dynamics Approach for Multisite Sampling of Many Ligands

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Free Energy Calculations

Background:

• Investigating multiple molecular perturbations is crucial for optimizing ligand design.
• Existing methods may have limitations in handling complex, multi-site substitutions.
• Accurate prediction of free energies guides structure-based drug design.

Purpose of the Study:

• To develop and present the discrete Gibbs sampler-based lambda-dynamics (d-GSλD) method.
• To enable the investigation of multiple functional group perturbations at various substitution sites.
• To evaluate the precision and accuracy of the d-GSλD method.

Main Methods:

• Development of the discrete Gibbs sampler-based lambda-dynamics (d-GSλD) method.
• Construction of discrete lambda states for multisite d-GSλD.
• Application of d-GSλD to compute hydration free energies and protein-ligand binding affinities.
• Comparison with Massively Parallel Simulation-based Lambda Dynamics (MSλD) calculations.

Main Results:

• Excellent agreement between d-GSλD and MSλD was observed for hydration and binding free energies.
• Mean unsigned errors were 0.12 kcal/mol for hydration and 0.22 kcal/mol for binding free energies.
• Good agreement with experimental data was achieved, with errors ranging from 0.5-0.7 kcal/mol.

Conclusions:

• The d-GSλD method is a precise and accurate approach for calculating free energy changes.
• d-GSλD is applicable to diverse molecular design challenges, including structure-based drug design.
• The study provides a comparison between d-GSλD and MSλD methodologies.