Multisite lambda dynamics (MSλD) is an innovative free energy method that solves a critical scalability issue observed with traditional free energy perturbation or thermodynamic integration (FEP/TI) methodologies. By allowing the alchemical coupling parameter (λ) to fluctuate continuously during a single molecular dynamics (MD) trajectory, MSλD can perturb between many molecular fragments attached to a common ligand core at multiple sites of substitution. Thus, tens to hundreds of relative free energy differences can be computed simultaneously. The ability to explore unprecedented amounts of chemical space has clear implications in advancing on-going computer aided drug design efforts. An example demonstration has shown that 512 unique HIV-RT protein-ligand binding affinities could be computed from only 1.3 µs of MD sampling and two unique simulations (ligand bound and unbound). Efficiency gains of MSλD over FEP/TI methods range from factors of 10 to 50, while no loss of statistical precision is observed from exploring large chemical spaces with this method. Soft-core potential and biasing potential replica exchange algorithms further facilitate both small and large molecular perturbations. Recently, the exploration of HIV-RT protein side chain mutations with MSλD has been initiated to explore the ability to predict changes in ligand binding affinities for drug resistant mutations, with a goal of performing concerted protein plus ligand perturbations to optimize ligand binding to multiple variant protein forms. In a drug discovery context, this method would enable co-optimization of a lead compound across several drug resistant forms of a drug target simultaneously.

Multisite lambda dynamics can compute precise free energies of binding in combinatorically large chemical spaces featuring ligand and protein perturbations

254th National Meeting (2017)

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