Browsing by Author "Hwa, Terence"

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    Coevolutionary signals across protein lineages help capture multiple protein conformations
    (National Academy of Sciences, 2013) Morcos, Faruck; Jana, Biman; Hwa, Terence; Onuchic, José Nelson
    A long-standing problem in molecular biology is the determination of a complete functional conformational landscape of proteins. This includes not only proteins’ native structures, but also all their respective functional states, including functionally important intermediates. Here, we reveal a signature of functionally important states in several protein families, using direct coupling analysis, which detects residue pair coevolution of protein sequence composition. This signature is exploited in a protein structure-based model to uncover conformational diversity, including hidden functional configurations. We uncovered, with high resolution (mean ∼1.9 Å rmsd for nonapo structures), different functional structural states for medium to large proteins (200–450 aa) belonging to several distinct families. The combination of direct coupling analysis and the structure-based model also predicts several intermediates or hidden states that are of functional importance. This enhanced sampling is broadly applicable and has direct implications in protein structure determination and the design of ligands or drugs to trap intermediate states.
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    Genomics-aided structure prediction
    (2012) Sulkowska, Joanna I.; Morcos, Faruck; Weigt, Martin; Hwa, Terence; Onuchic, José N.; National Science Foundation; Center for Theoretical Biological Physics
    We introduce a theoretical framework that exploits the everincreasing genomic sequence information for protein structure prediction. Structure-based models are modified to incorporate constraints by a large number of non-local contacts estimated from direct coupling analysis (DCA) of co-evolving genomic sequences. A simple hybrid method, called DCA-fold, integrating DCA contacts with an accurate knowledge of local information (e.g., the local secondary structure) is sufficient to fold proteins in the range of 1–3 Å resolution.