Internal Bonding in Proteins

蛋白质的内键合

• 批准号: 7924924
• 负责人: HAROLD A. SCHERAGA
• 金额: $ 19.87万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924924
• 关键词: Accounting; Algorithms; Biological; CASP5 gene; CASP6 gene; Complex; Coupling; Databases; Development; Disease; Entropy; Exercise; Free Energy; Freedom; Goals; Grant; Homology Modeling; Hour; Kinetics; Lead; Mechanics; Methods; Modeling; Molecular Conformation; Mutation; Nucleic Acids; Oncogenic; Operative Surgical Procedures; Pathway interactions; Performance; Physics; Play; Positioning Attribute; Potential Energy; Procedures; Property; Protein Conformation; Proteins; Research; Research Personnel; Role; Running; Solvents; Staging; Structure; Testing; Time; Training; Work; amyloid formation; base; beta pleated sheet; blind; conformational conversion; globular protein; improved; innovation; knowledge base; millisecond; molecular dynamics; neglect; polypeptide; programs; protein complex; protein folding; protein structure; protein structure prediction; simulation; theories; three dimensional structure; virtual

Our long-term objective is to identify how protein conformation plays a role in various diseases. Our specific aims are to compute the 3D structures of proteins, protein-protein and protein-nucleic acid complexes, and the folding pathways leading to these entities, using a hierarchical physics-based method. Extensive conformational search is performed with our united-residue (UNRES) force field, in which a polypeptide chain is represented as a virtual-bond C(alpha)-C(alpha) and C(alpha)-SC chain, and the resulting conformations are converted to an all-atom representation and refined at the all-atom level. UNRES has been derived as a restricted free energy function of united-residue chains averaged over the degrees of freedom that are lost when passing to the virtual-bond geometry. Kubo's cluster cumulant theory has been used to derive analytical expressions for the respective free-energyterms, which enabled us to express the multibody terms analytically, which are essential for reproducing regular alpha-helical and beta-sheet structures. Our approach was successful in two recent blind protein structure prediction tests: CASP5 and CASP6; we predicted complete structures of four targets of which two were alpha-helical and two were alpha/beta proteins, and large segments of other targets. We made a start on predicting folding pathways by implementing Langevin dynamics for the UNRES force field. Using UNRES/MD, we folded a 75-residue protein from the extended conformation to the native structure in about 5 hours on a single processor; this means that UNRES/MD provides a 10,000 fold increase in the time scale compared to all-atom MD and is a practical method for studying protein-folding pathways up to the millisecond scale. The UNRES/MD approach, however, suffers from the neglect of configurational entropy in the present parameterization. We will rectify this deficiency by revising the parameterization of UNRES. We will also further develop: (a) our global-optimization algorithms by replacing local minimization with short MD runs, thereby incorporating configurational entropy, (b) our all-atom force field, and (c) a method to convert UNRES folding pathways to all-atom pathways. We will also extend the UNRES approach to derive a united-residue physics-based force field to study protein-nucleic acid interactions.

我们的长期目标是确定蛋白质构象如何在各种疾病中发挥作用。我们的具体