Predicting the Effect of Mutations on Protein-Protein Binding Interactions through Structure-Based Interface Profiles

被引:105
作者
Brender, Jeffrey R. [1 ]
Zhang, Yang [1 ,2 ]
机构
[1] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA
关键词
COMPUTATIONAL DESIGN; MUTANT PROTEIN; AFFINITY; EVOLUTIONARY; REGIONS; FORCE; SIMILARITY; ENERGETICS; STABILITY; COMPLEXES;
D O I
10.1371/journal.pcbi.1004494
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
The formation of protein-protein complexes is essential for proteins to perform their physiological functions in the cell. Mutations that prevent the proper formation of the correct complexes can have serious consequences for the associated cellular processes. Since experimental determination of protein-protein binding affinity remains difficult when performed on a large scale, computational methods for predicting the consequences of mutations on binding affinity are highly desirable. We show that a scoring function based on interface structure profiles collected from analogous protein-protein interactions in the PDB is a powerful predictor of protein binding affinity changes upon mutation. As a standalone feature, the differences between the interface profile score of the mutant and wild-type proteins has an accuracy equivalent to the best all-atom potentials, despite being two orders of magnitude faster once the profile has been constructed. Due to its unique sensitivity in collecting the evolutionary profiles of analogous binding interactions and the high speed of calculation, the interface profile score has additional advantages as a complementary feature to combine with physics-based potentials for improving the accuracy of composite scoring approaches. By incorporating the sequence-derived and residue-level coarse-grained potentials with the interface structure profile score, a composite model was constructed through the random forest training, which generates a Pearson correlation coefficient >0.8 between the predicted and observed binding free-energy changes upon mutation. This accuracy is comparable to, or outperforms in most cases, the current best methods, but does not require high-resolution full-atomic models of the mutant structures. The binding interface profiling approach should find useful application in human-disease mutation recognition and protein interface design studies.
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页数:25
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