Cited by 56Protein Structure and DynamicsComputational Drug Discovery MethodsMachine Learning in Bioinformatics

A multiscale approach to predicting affinity changes in protein-protein interfaces: Multiscale Method for Predicting ΔΔG

Dourado, Daniel F. A. R., Flores, Samuel Coulbourn·2014·Proteins: Structure, Function, and Bioinformatics

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.

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Crossref · 10.1002/prot.24634

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Authors
Dourado, D. F. A. R., & Flores, S. C.
Affiliations
Uppsala University (SE)
Corresponding author
Flores, Samuel Coulbourn
Venue
Proteins: Structure, Function, and Bioinformatics
Publisher
Wiley
Published
2014-07-05
Volume
82
Issue
10
Pages
2681-2690
ISSN
0887-3585 (ISSN-L)
OpenAlex
W2163052596
Cited by
56
References
47
Citations by year
2026: 3 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 8 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 1
FWCI
2.05
Type
journal article
Language
en
Open access
closed
Locations
  • Proteins Structure Function and Bioinformatics (publishedVersion)
  • PubMed (publishedVersion)
Funders
eSSENCE (essenceofscience.se)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
Keywords
protein-protein interfaces, binding affinity prediction, substitution mutations, multiscale modeling, knowledge-based potentials, conformational flexibility, protein complexes, ΔΔG, point mutations
MeSH terms
Animals, Artificial Intelligence, Expert Systems, Humans, Kinetics, Models, Molecular, Protein Conformation, Proteins, Software Validation, Statistics as Topic, Point Mutation, Crystallography, X-Ray, Entropy, Computational Biology, Amino Acid Substitution, Internet, Databases, Protein, Multiprotein Complexes, Protein Interaction Domains and Motifs, Protein Stability

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