Context-Based Identification of Protein-Protein Interfaces and “Hot-Spot” Residues

Geppert, Tim; Hoy, Benjamin; Wessler, Silja; Schneider, Gisbert

doi:10.1016/j.chembiol.2011.01.005

Cited by 80Protein Structure and DynamicsMachine Learning in BioinformaticsComputational Drug Discovery Methods

Context-Based Identification of Protein-Protein Interfaces and “Hot-Spot” Residues

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Geppert, Tim, Hoy, Benjamin, Wessler, Silja, Schneider, Gisbert·2011·Chemistry & Biology

DOI 10.1016/j.chembiol.2011.01.005

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Abstract

Reliable determination of protein-protein interaction sites is of critical importance for structure-based design of small molecules modulating protein function through macromolecular interfaces. We present an alignment-free computational method for prediction of protein-protein interface residues. The method ("iPred") is based on a knowledge-based scoring function adapted from the field of protein folding and small molecule docking. Based on a training set of 394 hetero-dimeric proteins iPred achieves sustained accuracy on an external unbound test set. Prediction robustness was assessed from more than 1500 diverse complexes containing homo- and hetero-dimers. The technique does not rely on sequence conservation, so that rapid interface identification is possible even for proteins for which homologs are unknown or lack conserved residue patterns in interface region. Functional "hot-spot" residues are enriched among the predicted interface residues, rendering the method predestined for macromolecular binding site identification and drug design studies aiming at modulating protein-protein interaction that might influence protein function. For a comparative structural model of peptidase HtrA from Helicobacter pylori, we performed mutation studies for predicted hot-spot residues, which were confirmed as functionally relevant for HtrA activity or oligomerization.

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Authors: Geppert, T., Hoy, B., Wessler, S., & Schneider, G.
Affiliations: ETH Zurich (CH)
University of Salzburg (AT)
Corresponding author: Schneider, Gisbert
ORCID: Wessler, Silja
Schneider, Gisbert
Venue: Chemistry & Biology
Publisher: Elsevier BV
Published: 2011-03
Volume: 18
Issue: 3
Pages: 344-353
ISSN: 1074-5521 (ISSN-L)
DOI: 10.1016/j.chembiol.2011.01.005
OpenAlex: W2056596940
Cited by: 80
References: 53
Citations by year: 2026: 4 · 2025: 8 · 2024: 2 · 2023: 9 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 2 · 2015: 5 · 2014: 9 · 2013: 6 · 2012: 7
FWCI: 3.38
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 869 d)
Locations: Chemistry & 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 › Machine Learning in Bioinformatics
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords: protein-protein interfaces, hot spot residues, knowledge-based scoring function, heterodimeric protein, protein-protein interaction, drug design, Helicobacter pylori, oligomerization
MeSH terms: Algorithms, Bacterial Proteins, Mutation, Peptide Hydrolases, Helicobacter pylori, Protein Structure, Tertiary, Protein Folding, Protein Interaction Mapping, Databases, Protein

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Context-Based Identification of Protein-Protein Interfaces and “Hot-Spot” Residues

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