Investigating Molecular Recognition and Accelerating Free Energy Calculations with Lambda Dynamics

Alchemical free energy (AFE) methods are popular in silico tools in structure-based drug design and are useful for studying the thermodynamic and structural properties of small molecule–protein and protein–protein interactions. λ-Dynamics (λD) is a unique AFE method that can investigate multiple functional group perturbations to a ligand core or protein sequence simultaneously within a single molecular dynamics simulation. As a result, changes in guest binding free energies to a target host can be mapped as a function of chemical group identity. Furthermore, the ability to calculate multiple relative binding free energies from a single λD calculation yields significant efficiency gains (5-30 times) compared to conventional AFE methods without compromising accuracy in the final free energy results. This talk will review our progress to advance λD-based techniques for modeling small molecule–protein binding, including the ability to model large and challenging perturbations accurately, and the introduction of new Gibbs sampler-based algorithms to further accelerate λD calculations. Finally, new advancements to model concerted protein-ligand mutations and large protein–protein complexes with λD will be discussed.