Modeling and fitting protein-protein complexes to predict change of binding energy
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 25406Article in journal (Refereed) PublishedText
It is possible to accurately and economically predict change in protein-protein interaction energy upon mutation (Delta Delta G), when a high-resolution structure of the complex is available. This is of growing usefulness for design of high-affinity or otherwise modified binding proteins for therapeutic, diagnostic, industrial, and basic science applications. Recently the field has begun to pursue Delta Delta G prediction for homology modeled complexes, but so far this has worked mostly for cases of high sequence identity. If the interacting proteins have been crystallized in free (uncomplexed) form, in a majority of cases it is possible to find a structurally similar complex which can be used as the basis for template-based modeling. We describe how to use MMB to create such models, and then use them to predict Delta Delta G, using a dataset consisting of free target structures, co-crystallized template complexes with sequence identify with respect to the targets as low as 44%, and experimental Delta Delta G measurements. We obtain similar results by fitting to a low-resolution Cryo-EM density map. Results suggest that other structural constraints may lead to a similar outcome, making the method even more broadly applicable.
Place, publisher, year, edition, pages
2016. Vol. 6, 25406
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-297785DOI: 10.1038/srep25406ISI: 000375797500001PubMedID: 27173910OAI: oai:DiVA.org:uu-297785DiVA: diva2:943599
FundereSSENCE - An eScience CollaborationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)