Alanine scanning is a widely used tool for probing protein-protein interactions. However, its computational implementation suffers from deficiencies, primary being its somewhat qualitative rather than quantitative performance. More significant is prediction of relative binding free energies is limited to alanine mutations only in contrast to methods such as TI.Mutational Locally Enhanced Sampling (MULES) is an extension of the LES method where the MD simulations include multiple copies of an individual region, each copy consisting of either a native or mutant structure. The mutant may be a natural or non-natural amino acid. Post processed MM-PBSA calculations then provide a ??G value for the mutation. For a prototypical set of mutations MULES has quantitatively predicted ??G values with a maximum unsigned error to experiment of 0.5 kcal/mol, whilst maintaining high precision and speed compared to alternative techniques. Mules has the potential to be applied systematically to full protein-protein interface studies.

MULES (Mutational Locally Enhanced Sampling) a new method for quantitative prediction of  relative binding free energies

243rd National Meeting (2012)

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