Protein-protein interactions are involved in a huge variety of cellular processes. Understanding their structural, dynamical and energetic basis is therefore of key importance to a number of research disciplines. Here we present a new computational method for predicting the effects of any mutation at a protein-protein interface, termed Mutational Locally Enhanced Sampling (MULES).MULES uses atomistic molecular dynamics simulations to predict the relative binding free energies (??G) for native and mutant complexes. For a prototypical set of mutations validated with experiment, MULES shows significantly improved accuracy in ??G prediction and high precision and speed compared to existing methods. In addition, MULES in principle allows the effect of any mutation to be calculated, whether natural or non-natural. The versatility, quantitative accuracy, high precision and speed of MULES enhance its potential for modelling changes to the interface in a systematic way, thereby aiding the direction and rationalisation of experimental work.

Quantitative prediction of the energetic and structural effects of mutations at protein-protein interfaces

243rd National Meeting (2012)

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