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Ab initio construction of polypeptide fragments: Efficient generation of accurate, representative ensembles
Author(s) -
DePristo Mark A.,
de Bakker Paul I. W.,
Lovell Simon C.,
Blundell Tom L.
Publication year - 2003
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10285
Subject(s) - dihedral angle , decoy , ab initio , chemistry , context (archaeology) , root mean square , algorithm , crystallography , physics , computer science , molecule , biology , paleontology , hydrogen bond , biochemistry , receptor , organic chemistry , quantum mechanics
Abstract We describe a novel method to generate ensembles of conformations of the main‐chain atoms {N, Cα, C, O, Cβ} for a sequence of amino acids within the context of a fixed protein framework. Each conformation satisfies fundamental stereo‐chemical restraints such as idealized geometry, favorable ϕ/ψ angles, and excluded volume. The ensembles include conformations both near and far from the native structure. Algorithms for effective conformational sampling and constant time overlap detection permit the generation of thousands of distinct conformations in minutes. Unlike previous approaches, our method samples dihedral angles from fine‐grained ϕ/ψ state sets, which we demonstrate is superior to exhaustive enumeration from coarse ϕ/ψ sets. Applied to a large set of loop structures, our method samples consistently near‐native conformations, averaging 0.4, 1.1, and 2.2 Å main‐chain root‐mean‐square deviations for four, eight, and twelve residue long loops, respectively. The ensembles make ideal decoy sets to assess the discriminatory power of a selection method. Using these decoy sets, we conclude that quality of anchor geometry cannot reliably identify near‐native conformations, though the selection results are comparable to previous loop prediction methods. In a subsequent study (de Bakker et al.: Proteins 2003;51:21–40), we demonstrate that the AMBER forcefield with the Generalized Born solvation model identifies near‐native conformations significantly better than previous methods. Proteins 2003;51:41–55. © 2003 Wiley‐Liss, Inc.