Modeling and fitting protein-protein complexes to predict change of binding energy.

Daniel F.A.R Dourado,Samuel Coulbourn Flores

doi:10.1038/srep25406

Daniel F.A.R Dourado, Samuel Coulbourn Flores

Open Access

https://doi.org/10.1038/srep25406

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Journal: Scientific Reports	Publication Date: May 1, 2016
Citations: 13	License type: CC BY 4.0

Affiliation: Uppsala University

Abstract

It is possible to accurately and economically predict change in protein-protein interaction energy upon mutation (ΔΔG), 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 ΔΔG 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 ΔΔG, 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 ΔΔG 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.

Highlights

There are limited options for computing Δ Δ G for the case in which the interacting proteins have only been crystallized in the free form
Specific cases in which the free structure is related to one of the proteins in the template complex include antibody-bound IGF-I30, human Chorionic Somatomammotropin[31] vs. human Growth Hormone (GH) Receptor, Fcγ RI vs. IgG132–34
In this work when we provide Root Mean Square Deviations (RMSDs) (Root Mean Square Deviation) we refer in all cases to the discrepancy in backbone 3D atomic structure of modeled vs. template complexes

Summary

Introduction

There are limited options for computing Δ Δ G for the case in which the interacting proteins have only been crystallized in the free form. For many such structures, low resolution density maps of their complex are available[22]. Template modeling uses a structural alignment, which can be done accurately even at low sequence identity[27,28]. This realization has led to considerable interest in template-based docking[29]. In this study we implement a fast and simple to use internal-coordinate template-based docking protocol in MMB19,20, that works even in the range of ~40% sequence identity for homologous proteins (quite near the twilight zone)[27,35] and extend ZEMu1 to predict Δ Δ G for -modeled and fitted complexes

Methods

Results

Conclusion