Multisite λ dynamics (MSλD) is a highly efficient and scalable alchemical free energy technique. MSλD requires fewer simulations and one to two orders of magnitude less simulation time to achieve comparable levels of precision with more established methods such as free energy perturbation and thermodynamic integration. MSλD is highly scalable, as a single simulation can compare a variety of systems, rather than being limited to pairwise comparisons like other techniques. Recently, MSλD accuracy has improved through a variety of technical advancements, including implicit constraints, biasing potential replica exchange, adaptive landscape flattening, and soft-core potentials. Following the pioneering work of Peter Kollman, we use MSλD to compute mutational changes in the folding free energy of T4 lysozyme. Folding free energies are computed for seven single site mutants with 3-9 sequences each, and for three multisite mutants comprising up to 240 alternative sequences. Correlation with experimental values is excellent. The slope of best fit is slightly steeper than unity suggesting that some residual structure remains in the unfolded ensemble which our simple pentapeptide model fails to capture. The ability of MSλD to accurately calculate changes in folding free energy holds great promise for the fields of protein design and evolutionary dynamics of protein sequences.

Multisite λ dynamics enables accurate and efficient calculation of mutational changes in the folding free energy of T4 lysozyme

254th National Meeting (2017)

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