Analyses of Mutation Displacements from Homology Models.

Evaluation of the structural perturbations introduced by a single amino acid mutation is the main issue for protein structural biology. We propose here to present some recent advances in methods, allowing the splitting of distortion between the actual substitution effect and the contribution of the local flexibility of the position where the mutation occurs. Its main drawback is the need of many structures with a single mutation in each of them. To bypass this difficulty, we propose to use molecular modeling tools, with several software enabling us to build a model from a template, given the sequence. As a proof of concept, we rely on a gold standard, the human lysozyme. Both wild-type and three mutant structures are available in the PDB. Two of these mutations result in amyloid fibril formation, and the last one is neutral. As a conclusion, irrespective of the algorithm used for modeling, side chain conformations at the site of mutation are reliable, although long-range effects are out of reach of these tools.