title: Direct-coupling analysis of residue coevolution captures native contacts across many protein families.
abstract: The similarity in the three-dimensional structures of homologous proteins imposes strong constraints on their sequence variability. It has long been suggested that the resulting correlations among amino acid compositions at different sequence positions can be exploited to infer spatial contacts within the tertiary protein structure. Crucial to this inference is the ability to disentangle direct and indirect correlations, as accomplished by the recently introduced direct-coupling analysis (DCA). Here we develop a computationally efficient implementation of DCA, which allows us to evaluate the accuracy of contact prediction by DCA for a large number of protein domains, based purely on sequence information. DCA is shown to yield a large number of correctly predicted contacts, recapitulating the global structure of the contact map for the majority of the protein domains examined. Furthermore, our analysis captures clear signals beyond intradomain residue contacts, arising, e.g., from alternative protein conformations, ligand-mediated residue couplings, and interdomain interactions in protein oligomers. Our findings suggest that contacts predicted by DCA can be used as a reliable guide to facilitate computational predictions of alternative protein conformations, protein complex formation, and even the de novo prediction of protein domain structures, contingent on the existence of a large number of homologous sequences which are being rapidly made available due to advances in genome sequencing.
authors: Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093-0374, USA.
authors: Faruck
authors: F
authors: Morcos
authors: Andrea
authors: A
authors: Pagnani
authors: Bryan
authors: B
authors: Lunt
authors: Arianna
authors: A
authors: Bertolino
authors: Debora S
authors: DS
authors: Marks
authors: Chris
authors: C
authors: Sander
authors: Riccardo
authors: R
authors: Zecchina
authors: José N
authors: JN
authors: Onuchic
authors: Terence
authors: T
authors: Hwa
authors: Martin
authors: M
authors: Weigt
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping / Q000379:methods; D055503:Protein Multimerization; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D000596:Amino Acids; D011506:Proteins