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Structural refinement of protein segments containing secondary structure elements: Local sampling, knowledge-based potentials, and clustering
Authors:Zhu Jiang  Xie Li  Honig Barry
Institution:Howard Hughes Medical Institute, Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biophysics, Columbia University, 1130 St. Nicholas Avenue, Room 815, New York, New York 10032, USA.
Abstract:In this article, we present an iterative, modular optimization (IMO) protocol for the local structure refinement of protein segments containing secondary structure elements (SSEs). The protocol is based on three modules: a torsion-space local sampling algorithm, a knowledge-based potential, and a conformational clustering algorithm. Alternative methods are tested for each module in the protocol. For each segment, random initial conformations were constructed by perturbing the native dihedral angles of loops (and SSEs) of the segment to be refined while keeping the protein body fixed. Two refinement procedures based on molecular mechanics force fields - using either energy minimization or molecular dynamics - were also tested but were found to be less successful than the IMO protocol. We found that DFIRE is a particularly effective knowledge-based potential and that clustering algorithms that are biased by the DFIRE energies improve the overall results. Results were further improved by adding an energy minimization step to the conformations generated with the IMO procedure, suggesting that hybrid strategies that combine both knowledge-based and physical effective energy functions may prove to be particularly effective in future applications.
Keywords:clustering algorithm  knowledge‐based potential  torsion space sampling  generalized Born model  secondary structure element  structure refinement
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