title: A multiscale approach to predicting affinity changes in protein-protein interfaces.
abstract: Substitution mutations in protein-protein interfaces can have a substantial effect on binding, which has consequences in basic and applied biomedical research. Experimental expression, purification, and affinity determination of protein complexes is an expensive and time-consuming means of evaluating the effect of mutations, making a fast and accurate in silico method highly desirable. When the structure of the wild-type complex is known, it is possible to economically evaluate the effect of point mutations with knowledge based potentials, which do not model backbone flexibility, but these have been validated only for single mutants. Substitution mutations tend to induce local conformational rearrangements only. Accordingly, ZEMu (Zone Equilibration of Mutants) flexibilizes only a small region around the site of mutation, then computes its dynamics under a physics-based force field. We validate with 1254 experimental mutants (with 1-15 simultaneous substitutions) in a wide variety of different protein environments (65 protein complexes), and obtain a significant improvement in the accuracy of predicted ΔΔG.
authors: Department of Cell and Molecular Biology, Computational and Systems Biology, Uppsala University, 751 24, Uppsala, Sweden.
authors: Daniel F A R
authors: DF
authors: Dourado
authors: Samuel Coulbourn
authors: SC
authors: Flores
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001185:Artificial Intelligence; D019295:Computational Biology; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D019277:Entropy; D005103:Expert Systems; D006801:Humans; D020407:Internet; D007700:Kinetics; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012986:Software Validation; D013223:Statistics as Topic
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins
keywords: affinity maturation; biologic design; internal coordinate mechanics; multiscale modeling