Please use this identifier to cite or link to this item: http://buratest.brunel.ac.uk/handle/2438/9775
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dc.contributor.authorFornili, A-
dc.contributor.authorPandini, A-
dc.contributor.authorLu, H-C-
dc.contributor.authorFraternali, F-
dc.date.accessioned2015-01-16T13:18:59Z-
dc.date.available2013-11-12-
dc.date.available2015-01-16T13:18:59Z-
dc.date.issued2013-
dc.identifier.citationJournal of Chemical Theory and Computation, 9:11, pp. 5127 - 5147, 2013en_US
dc.identifier.issn1549-9618-
dc.identifier.urihttp://pubs.acs.org/doi/abs/10.1021/ct400486p-
dc.identifier.urihttp://bura.brunel.ac.uk/handle/2438/9775-
dc.description.abstractThe ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society.en_US
dc.format.extent5127 - 5147-
dc.languageeng-
dc.language.isoenen_US
dc.subjectProteinsen_US
dc.subjectPartners (hubs)en_US
dc.subjectIntrinsic disorderen_US
dc.titleSpecialized dynamical properties of promiscuous residues revealed by simulated conformational ensemblesen_US
dc.typeArticleen_US
dc.identifier.doihttp://dx.doi.org/10.1021/ct400486p-
dc.relation.isPartOfJournal of Chemical Theory and Computation-
dc.relation.isPartOfJournal of Chemical Theory and Computation-
pubs.organisational-data/Brunel-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Engineering, Design and Physical Sciences-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Engineering, Design and Physical Sciences/Dept of Computer Science-
pubs.organisational-data/Brunel/Brunel Staff by College/Department/Division/College of Engineering, Design and Physical Sciences/Dept of Computer Science/Computer Science-
Appears in Collections:Biological Sciences
Dept of Life Sciences Research Papers

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