title: Finding Our Way in the Dark Proteome.
abstract: The traditional structure-function paradigm has provided significant insights for well-folded proteins in which structures can be easily and rapidly revealed by X-ray crystallography beamlines. However, approximately one-third of the human proteome is comprised of intrinsically disordered proteins and regions (IDPs/IDRs) that do not adopt a dominant well-folded structure, and therefore remain "unseen" by traditional structural biology methods. This Perspective considers the challenges raised by the "Dark Proteome", in which determining the diverse conformational substates of IDPs in their free states, in encounter complexes of bound states, and in complexes retaining significant disorder requires an unprecedented level of integration of multiple and complementary solution-based experiments that are analyzed with state-of-the art molecular simulation, Bayesian probabilistic models, and high-throughput computation. We envision how these diverse experimental and computational tools can work together through formation of a "computational beamline" that will allow key functional features to be identified in IDP structural ensembles.
authors.forename: Asmit
authors.initials: A
authors.lastname: Bhowmick
authors.forename: David H
authors.initials: DH
authors.lastname: Brookes
authors.forename: Shane R
authors.initials: SR
authors.lastname: Yost
authors.affiliation: Department of Integrative Structural and Computational Biology, Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: H Jane
authors.initials: HJ
authors.lastname: Dyson
authors.affiliation: Molecular Structure and Function Program, Hospital for Sick Children , Toronto, Ontario M5G 0A4, Canada.|Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Julie D
authors.initials: JD
authors.lastname: Forman-Kay
authors.forename: Daniel
authors.initials: D
authors.lastname: Gunter
authors.forename: Martin
authors.initials: M
authors.lastname: Head-Gordon
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Hura
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305, United States.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
authors.forename: David E
authors.initials: DE
authors.lastname: Wemmer
authors.affiliation: Department of Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Wright
authors.forename: Teresa
authors.initials: T
authors.lastname: Head-Gordon
mesh_terms: D001499:Bayes Theorem; D002850:Chromatography, Gel; D019295:Computational Biology; D018360:Crystallography, X-Ray; D015894:Genome, Human; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D011336:Probability; D011487:Protein Conformation; D017510:Protein Folding; D020543:Proteome; D040901:Proteomics / Q000379:methods; D012984:Software
chemical_list: D064267:Intrinsically Disordered Proteins; D020543:Proteome