title: Prediction of protein structure by simulating coarse-grained folding pathways: a preliminary report.
abstract: A set of software tools designed to study protein structure and kinetics has been developed. The core of these tools is a program called Folding Machine (FM) which is able to generate low resolution folding pathways using modest computational resources. The FM is based on a coarse-grained kinetic ab initio Monte-Carlo sampler that can optionally use information extracted from secondary structure prediction servers or from fragment libraries of local structure. The model underpinning this algorithm contains two novel elements: (a) the conformational space is discretized using the Ramachandran basins defined in the local phi-psi energy maps; and (b) the solvent is treated implicitly by rescaling the pairwise terms of the non-bonded energy function according to the local solvent environments. The purpose of this hybrid ab initio/knowledge-based approach is threefold: to cover the long time scales of folding, to generate useful 3-dimensional models of protein structures, and to gain insight on the protein folding kinetics. Even though the algorithm is not yet fully developed, it has been used in a recent blind test of protein structure prediction (CASP5). The FM generated models within 6 A backbone rmsd for fragments of about 60-70 residues of alpha-helical proteins. For a CASP5 target that turned out to be natively unfolded, the trajectory obtained for this sequence uniquely failed to converge. Also, a new measure to evaluate structure predictions is presented and used along the standard CASP assessment methods. Finally, recent improvements in the prediction of beta-sheet structures are briefly described.
authors.affiliation: Searle Chemistry Lab, University of Chicago, 5735 South Ellis Ave #126, Chicago, Illinois 60637, USA. acolubri@uchicago.edu
authors.forename: Andrés
authors.initials: A
authors.lastname: Colubri
mesh_terms: D000465:Algorithms; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D020539:Sequence Analysis, Protein / Q000379:methods*; D013997:Time Factors
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C094064:gliotactin; C099217:CASP5 protein, human; D020169:Caspases; D003546:Cysteine Endopeptidases