Cited by 1,728Protein Structure and DynamicsRNA and protein synthesis mechanismsEnzyme Structure and Function

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Predicting Changes in the Stability of Proteins and Protein Complexes: A Study of More Than 1000 Mutations

Guerois, Raphael, Nielsen, Jens Erik, Serrano, Luis·2002·Journal of Molecular Biology

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Abstract

We have developed a computer algorithm, FOLDEF (for FOLD-X energy function), to provide a fast and quantitative estimation of the importance of the interactions contributing to the stability of proteins and protein complexes. The predictive power of FOLDEF was tested on a very large set of point mutants (1088 mutants) spanning most of the structural environments found in proteins. FOLDEF uses a full atomic description of the structure of the proteins. The different energy terms taken into account in FOLDEF have been weighted using empirical data obtained from protein engineering experiments. First, we considered a training database of 339 mutants in nine different proteins and optimised the set of parameters and weighting factors that best accounted for the changes in stability of the mutants. The predictive power of the method was then tested using a blind test mutant database of 667 mutants, as well as a database of 82 protein-protein complex mutants. The global correlation obtained for 95 % of the entire mutant database (1030 mutants) is 0.83 with a standard deviation of 0.81 kcal mol(-1) and a slope of 0.76. The present energy function uses a minimum of computational resources and can therefore easily be used in protein design algorithms, and in the field of protein structure and folding pathways prediction where one requires a fast and accurate energy function. FOLDEF is available via a web-interface at http://fold-x.embl-heidelberg.de

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Result
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Method
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Method
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“[7,8,9] Current algorithms for protein redesign, in contrast, are not directly trained on experimentally measured effects, but rather indirect measures such as sequence recovery ( i . e . the ability to recapitulate a known active site after running a design simulation).”
Background
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“Next, we identified docking models that meet the following criteria: (1) the interaction involves both the N-domain (residues 13–73) and C-terminal domain (residues 74–190); (2) the OSTF1-binding surface does not overlap with the known SH3-binding pocket (residues 21–24, 26–30, 35, 46–49, 60, 62, 64–65, 68–69); (3) no…”
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Large‐scale analysis of somatic hypermutations in antibodies reveals which structural regions, positions and amino acids are modified to improve affinity
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Method
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Method
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“Only in speciﬁcity, FOLDEF and MINERVA2”
MethodResultInfluential
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Method
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“The resulting mean energy is expressed in kcal/mol, and the prediction decision on whether the mutation destabilizes structure is based upon Schymkowitz et al.43 and Guirois et al.44 where severely reduced structural stability DDG is considered to be >1.6 kcal/mol.”
BackgroundInfluential
Average assignment method for predicting the stability of protein mutants
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Four-Body Scoring Function for Mutagenesis
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Structural Basis of Affinity Maturation and Intramolecular Cooperativity in a Protein-Protein Interaction
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Molecular Determinants of Mutant Phenotypes, Inferred from Saturation Mutagenesis Data
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“…saturation mutagenesis studies can be used to improve predictions of effects of nonsynonymous single nucleotide polymorphisms on protein activity (Guerois et al. 2002; Randles et al. 2006; Yue and Moult 2006; Bromberg et al. 2008; Radivojac et al. 2013) as well as for protein threading…”
Background
Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia
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“We also estimated protein stability changes using the program FoldX [70] based on the crystal structure (PDB ID: 3r05).”
Method

Authors: Guerois, R., Nielsen, J. E., & Serrano, L.
Affiliations: Howard Hughes Medical Institute (US)
European Molecular Biology Laboratory (DE)
ORCID: Nielsen, Jens Erik
Serrano, Luis
Venue: Journal of Molecular Biology
Publisher: Elsevier BV
Published: 2002-07
Volume: 320
Issue: 2
Pages: 369-387
ISSN: 0022-2836 (ISSN-L)
DOI: 10.1016/s0022-2836(02)00442-4
OpenAlex: W2092387745
Cited by: 1,728
References: 95
Citations by year: 2026: 68 · 2025: 85 · 2024: 61 · 2023: 78 · 2022: 74 · 2021: 90 · 2020: 98 · 2019: 82 · 2018: 90 · 2017: 84 · 2016: 94 · 2015: 93 · 2014: 90 · 2013: 102 · 2012: 87
FWCI: 12.09
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Molecular Biology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords: protein stability prediction, point mutations, protein-protein complex, parameter optimization, protein design, protein folding pathways
MeSH terms: Algorithms, Hydrogen Bonding, Models, Genetic, Mutation, Protein Conformation, Proteins, Software, Thermodynamics, Water, Models, Statistical, Point Mutation, Protein Structure, Secondary, Protein Folding, Databases as Topic

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Predicting Changes in the Stability of Proteins and Protein Complexes: A Study of More Than 1000 Mutations

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