A multiscale approach to predicting affinity changes in protein-protein interfaces: Multiscale Method for Predicting ΔΔG
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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Empirical energy-based methods usually take linear forms, often with only energy-based terms, and fail to exploit evolution information, which can limit their ability to capture mutation effects on binding affinity.
“They usually take a form of linear functions, often with only energy‐based terms, and fail to exploit evolution information, which can limit their ability to capture mutation effects on binding affinity.”
From iSEE: Interface structure, evolution, and energy-based machine learning predictor of binding affinity changes upon mutations (2019) · cites this paper as [7]
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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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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