Sangam: A Confluence of Knowledge Streams

Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles

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dc.creator Fornili, A
dc.creator Pandini, A
dc.creator Lu, H-C
dc.creator Fraternali, F
dc.date 2015-01-16T13:18:59Z
dc.date 2013-11-12
dc.date 2015-01-16T13:18:59Z
dc.date 2013
dc.date.accessioned 2022-05-25T14:53:39Z
dc.date.available 2022-05-25T14:53:39Z
dc.identifier Journal of Chemical Theory and Computation, 9:11, pp. 5127 - 5147, 2013
dc.identifier 1549-9618
dc.identifier http://pubs.acs.org/doi/abs/10.1021/ct400486p
dc.identifier http://bura.brunel.ac.uk/handle/2438/9775
dc.identifier http://dx.doi.org/10.1021/ct400486p
dc.identifier.uri http://localhost:8080/xmlui/handle/CUHPOERS/172685
dc.description The 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.
dc.format 5127 - 5147
dc.language eng
dc.language en
dc.relation Journal of Chemical Theory and Computation
dc.relation Journal of Chemical Theory and Computation
dc.subject Proteins
dc.subject Partners (hubs)
dc.subject Intrinsic disorder
dc.title Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles
dc.type Article


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