Project

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Molecular evolution for structural biology: analyzing and predicting protein-protein interactions

Applicant Capitani Guido
Number 140879
Funding scheme Project funding (Div. I-III)
Research institution Paul Scherrer Institut
Institution of higher education Paul Scherrer Institute - PSI
Main discipline Biophysics
Start/End 01.11.2012 - 31.10.2015
Approved amount 314'411.00
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Keywords (5)

Protein-protein interactions; Protein crystallography; Structural bioinformatics; Molecular evolution; Crystal contacts

Lay Summary (English)

Lead
Lay summary

Describing the structure and interactions of proteins is a key prerequisite to the understanding of living systems. The main technique to determine protein structure, macromolecular crystallography, has profited from technological advances that greatly increased its power to tackle even the largest and most complicated proteins and complexes thereof. A drawback however remains: protein structures are determined by crystallography in the context of a crystal lattice, where the protein molecules are in contact through several interfaces. These interfaces can be of two types: those present in the native protein in solution (biologically relevant ones) and those that help to form the crystal lattice (crystal contacts). It is essential to recognize which of those interfaces are biologically relevant, since this determines the kind of assembly of the protein in its physiological environment. Crystallography per se provides no information about this. Experimentally, the problem can only be solved by resorting to time-consuming biophysical experiments.

The aim of this project is to develop an efficient, general and easy-to-use computational approach to the above problem, based on the most fundamental difference between biological interfaces and crystal contacts:  biological interfaces are the result of evolution, while crystal contacts are not. A protein interface classifier that detects the evolutionary signature present in biological interfaces is going to be very useful not only in the interpretation of protein crystal structures but also in “so-called” hybrid approaches where crystallography is employed in combination with other techniques like electron microscopy. In a second phase of the project we aim to apply the concepts of our interface classifier to protein-protein interface prediction. This will be of interest especially for structural genomics initiatives, which often produce structures of proteins before knowledge about their function and interaction partners is available.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Name Institute

Employees

Publications

Publication
Functional roles of the hexamer organization of plant glutamate decarboxylase.
Astegno Alessandra, Capitani Guido, Dominici Paola (2015), Functional roles of the hexamer organization of plant glutamate decarboxylase., in Biochimica et biophysica acta, 1854(9), 1229-1237.
Understanding the fabric of protein crystals: computational classification of biological interfaces and crystal contacts
Capitani Guido, Duarte Jose M., Baskaran Kumaran, Bliven Spencer, Somody Joseph C. (2015), Understanding the fabric of protein crystals: computational classification of biological interfaces and crystal contacts, in Bioinformatics (Oxford), 1.
A PDB-wide, evolution-based assessment of protein-protein interfaces.
Baskaran Kumaran, Duarte Jose M, Biyani Nikhil, Bliven Spencer, Capitani Guido (2014), A PDB-wide, evolution-based assessment of protein-protein interfaces., in BMC structural biology, 14(1), 22-22.
Conformational transitions driven by pyridoxal-5'-phosphate uptake in the psychrophilic serine hydroxymethyltransferase from Psychromonas ingrahamii.
Angelaccio Sebastiana, Dworkowski Florian, Di Bello Angela, Milano Teresa, Capitani Guido, Pascarella Stefano (2014), Conformational transitions driven by pyridoxal-5'-phosphate uptake in the psychrophilic serine hydroxymethyltransferase from Psychromonas ingrahamii., in Proteins, 82(10), 2831-41.
Structural basis for -10 promoter element melting by environmentally induced sigma factors.
Campagne Sébastien, Marsh May E, Capitani Guido, Vorholt Julia A, Allain Frédéric H-T (2014), Structural basis for -10 promoter element melting by environmentally induced sigma factors., in Nature structural & molecular biology, 21(3), 269-76.
An analysis of oligomerization interfaces in transmembrane proteins
Duarte José M., Biyani Nikhil, Baskaran Kumaran, Capitani Guido (2013), An analysis of oligomerization interfaces in transmembrane proteins, in BMC Structural Biology, 13(1), 21.
Quaternary dynamics of the SecA motor drive translocase catalysis.
Gouridis Giorgos, Karamanou Spyridoula, Sardis Marios Frantzeskos, Schärer Martin Alexander, Capitani Guido, Economou Anastassios (2013), Quaternary dynamics of the SecA motor drive translocase catalysis., in Molecular cell, 52(5), 655-66.
Protein interface classification by evolutionary analysis.
Duarte Jose M, Srebniak Adam, Schärer Martin A, Capitani Guido (2012), Protein interface classification by evolutionary analysis., in BMC bioinformatics, 13, 334.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
GTCBio Protein-protein interaction conference 2015 Talk given at a conference A “big data” approach to understanding protein-protein contacts 22.10.2015 Boston, United States of America Capitani Guido;
3DSIG 2015: Structural Bioinformatics and Computational Biophysics Talk given at a conference Understanding the fabric of protein crystals: a PDB-wide approach (Keynote) 10.07.2015 Dublin, Ireland Capitani Guido;
4th Nanomem Course - Membrane Protein Crystallisation, Paul Scherrer Institute Individual talk Lattice contacts and biological interfaces: understanding the fabric of protein (nano)-crystals 24.11.2014 Villigen PSI, Switzerland Capitani Guido;
Systems and Structural Views of Biology seminar, Rutgers University Individual talk Analyzing protein-protein interfaces and crystal contacts at the PDB-wide level 27.10.2014 Rutgers University, Piscataway, United States of America Capitani Guido;
GTCBio Protein-protein interaction conference 2014 Talk given at a conference A Systematic Analysis of Oligomerization Interfaces in Transmembrane Proteins: Implications for GPCR Dimerization 23.10.2014 Boston, United States of America Capitani Guido;
Structural Biology seminar, Purdue University Individual talk Analyzing protein-protein contacts at the PDB-wide level 22.10.2014 Purdue University, West Lafayette, United States of America Capitani Guido;
2014: Crystal (cl)Year (joint event with NETTAB 2014) Talk given at a conference Understanding interfaces in protein crystals: evolution comes to the rescue 16.10.2014 Turin, Italy Duarte Gamero Jose Manuel;
NETTAB 2014 From structural bioinformatics to integrative systems biology Talk given at a conference Understanding protein–protein contacts on a PDB-wide scale 15.10.2014 Turin, Italy Capitani Guido;
Invited seminar, Novartis Institutes for Biomedical Research Individual talk Biological interface or crystal contact? A PDB-wide analysis 08.10.2014 Novartis Institutes for Biomedical Research, Basel, Switzerland Capitani Guido;
28th Rhine-Knee Regional Meeting on Biocrystallography Individual talk A PDB-wide analysis of protein-protein contacts 24.09.2014 Mont Sainte Odile, France Baskaran Kumaran;
Protein assemblies at the interface of functionalised materials (CECAM Workshop) Talk given at a conference Protein-Protein Interface Classification By Evolutionary Analysis: Implications for Protein Assembly Interaction with Functionalized Surfaces 17.09.2014 Lausanne, Switzerland Capitani Guido;
ISMB 2014 (Intelligent Systems for Molecular Biology) conference Poster An analysis of oligomerization interfaces in transmembrane proteins 13.07.2014 Boston, United States of America Duarte Gamero Jose Manuel; Capitani Guido;
3DSIG 2014: Structural Bioinformatics and Computational Biophysics Poster EPPIC, a web tool to study protein crystal structures in their evolutionary context 11.07.2014 Boston, United States of America Duarte Gamero Jose Manuel; Capitani Guido;
Basel Computational Biology Seminar Individual talk An Analysis of Oligomerization Interfaces in Transmembrane Proteins 23.06.2014 Biozentrum Basel, Switzerland Capitani Guido;
28th Molecular Modeling Workshop Talk given at a conference Oligomeric interfaces in transmembrane proteins: an analysis 17.03.2014 Erlangen, Germany Capitani Guido;
GTCBio Protein-protein interaction conference Talk given at a conference Biologically Relevant PPI or Crystal Contact? Answers from Evolution and Geometry 24.10.2013 San Diego, United States of America Capitani Guido;
Recent Advances in Macromolecular Crystallization 2013 (RAMC 2013) Talk given at a conference Distinguishing biologically relevant interfaces from lattice contacts in protein crystals 08.09.2013 Le Bischemberg, France Capitani Guido;
International conference Bioinformatics 2013/BIT13 Talk given at a conference Is it biologically relevant? An evolution- and geometry-based protein interface classification approach 26.06.2013 Torun, Poland Capitani Guido;
11th BITS (Bioinformatics ITalian Society) meeting Talk given at a conference Protein interface classification by evolution and geometry: principles and applications 21.05.2013 University of Udine, Italy Capitani Guido;
27th Molecular Modeling Workshop Talk given at a conference Protein interface classification by evolutionary analysis 25.02.2013 University of Erlangen, Germany Capitani Guido;
PPI-Net International Conference Talk given at a conference Is it biologically relevant? Evolutionary protein-protein interface classification 16.01.2013 The Royal Society, London, Great Britain and Northern Ireland Capitani Guido;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions 100 years of X-ray crystallography International 2014

Abstract

Structural biology is currently enjoying a “golden age” of productivity thanks to a number of technological and conceptual advances, especially in the fields of macromolecular crystallography, biomolecular NMR and electron microscopy. Researchers are now able to determine the high-resolution structure of remarkably complex macromolecular entities, often consisting of many components arranged in novel ways. In the vast majority of the cases these macromolecular complex structures are obtained by protein crystallography and a particular problem emerges: it becomes increasingly difficult to decide by visual inspection which ones of the many interfaces observed in the crystal lattice are biologically relevant and which ones just mediate crystal contacts. Computational tools are therefore needed that are able to reliably identify the nature of each macromolecular interface in a crystal lattice as biological or crystal contact. The proposer has conceived and partly developed, with funding support from the PSI Forschungskommission, a novel approach to this problem, based on molecular evolution concepts. A proof-of-concept of the method, called CRK, has been published (Schärer et al., 2010). A second, more advanced version of CRK and a web server are being developed but new funding is now essential for a successful development of the project. This proposal deals with further increasing the performance and applicability of the method, exploring its potential for prediction of protein binding sites and establishing it as one of the standards for the analysis of protein-protein interfaces in the structural biology and structural bioinformatics communities.
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