Internal Bonding in Proteins

蛋白质的内键合

• 批准号: 7390702
• 负责人: HAROLD A. SCHERAGA
• 金额: $ 45.41万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-01-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390702
• 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; Object Attachment; 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 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起作用。我们的具体 目的是计算蛋白质，蛋白质 - 蛋白质和蛋白质核酸络合物的3D结构，以及 使用基于层次物理的方法，通向这些实体的折叠途径。广泛的 构象搜索是通过我们的统一保留（UNRER RER RER RER RER RER RER RER RER RER RES）进行的，其中多肽 链被表示为虚拟键C（alpha）-c（alpha）和c（alpha）-sc链，以及结果 构象转换为全原子表示，并在全原子级别进行完善。未恢复 被推导为在整个程度上平均的统一遗留链的限制自由能函数 传递到虚拟键几何形状时丢失的自由。久保的集群累积理论已经 用于得出各自的自由能的分析表达式，这使我们能够表达 分析多体术语，这对于重现常规α-螺旋和β-片至关重要 结构。我们的方法在最近的两个盲蛋白结构预测测试中取得了成功：CASP5和 casp6;我们预测了四个目标的完整结构，其中两个是α-螺旋，两个是 α/β蛋白和其他靶标的大部分。我们开始通过 为Unres Force Field实施Langevin动力学。使用UNRES/MD，我们折叠了75个残基 蛋白质从延长构象到单个处理器的大约5小时内到天然结构；这 意味着UNRIS/MD与All-Atom MD相比，时间尺度增加了10,000倍，是一个 研究蛋白质折叠途径至毫秒量表的实用方法。 UNRES/MD 但是，方法遭受了当前参数化中对配置熵的忽视。我们 将通过修改UNRER的参数化来纠正这种缺陷。我们还将进一步发展：（a）我们 通过用短MD运行替换本地最小化，全球优化算法，从而结合 配置熵，（b）我们的全原子力场，（c）将未折叠途径转换为 全原子途径。我们还将扩展开展基于统一的物理力量的UNRER RRES方法 研究蛋白核酸相互作用的领域。