A Simplified Potential for Protein Folding Simulations

蛋白质折叠模拟的简化潜力

• 批准号: 6929456
• 负责人: HAROLD A. SCHERAGA
• 金额: $ 3.56万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929456
• 关键词: chemical models; computer assisted sequence analysis; computer program /software; computer simulation; conformation; intermolecular interaction; mathematical model; protein folding; protein sequence; structural biology; thermodynamics; chemical models; computer assisted sequence analysis; computer program /software; computer simulation; conformation; intermolecular interaction; mathematical model; protein folding; protein sequence; structural biology; thermodynamics

DESCRIPTION (provided by applicant): The functioning of living organisms is largely dependent on the fact that each of its constituent proteins adopts a unique structure (the so-called native structure) under physiological conditions; this structure is determined by amino-acid sequence and its environment. According to Anfinsen's thermodynamic hypothesis, the native conformation of a protein is a global-energy minimum on its free-energy hypersurface. The native structure can therefore be sought as the global minimum in this hypersurface, if an accurate potential energy function is available. The shape of the free-energy hypersurface of proteins is very complex and difficult to describe. For efficiency reasons, simplified models of polypeptide chains, in which each amino-acid residue is represented by one or a few interaction sites rather than all-atom resolution models, must be used. While our previous focus was on global optimization methods, it is now focused on our physics-based united-residue UNRES potential-energy function. The main goal is to predict the structure of proteins of all major structural classes (alpha, beta, alpha+beta and alpha/beta) with chain lengths of up to 200 amino-acid residues within 4-6 Angstrom root mean square deviation based solely on global optimization of the potential energy. This will be accomplished by improving the functional forms and parameters of individual energy components and assuring the folding property of the potential by optimizing the total energy function to reflect the energetic hierarchy of partially unfolded structures. Understanding of the role of physical interactions in the formation of the native structur e of the protein will enable us not only to predict the final structure of the protein based only on knowledge of the amino-acid sequence but can be used to study protein folding or misfolding processes. The ability to predict three-dimensional structures of proteins or to predict their folding pathways can greatly contribute to rational drug design against cancer, Alzheimer or prion deseases.

描述（由申请人提供）： 生物体的功能在很大程度上取决于以下事实：其每个组成蛋白在生理条件下采用独特的结构（所谓的天然结构）。该结构取决于氨基酸序列及其环境。根据Anfinsen的热力学假设，蛋白质的天然构象是其自由能超表面上的全球能量最小值。因此，如果有准确的势能函数，则可以在该超表面中寻找天然结构作为全局最小值。蛋白质的自由能超表面的形状非常复杂且难以描述。出于效率原因，必须使用每个氨基酸残基由一个或几个相互作用位点而不是全原子分辨率模型表示的多肽链的简化模型。虽然我们以前的重点是全球优化方法，但现在它专注于我们基于物理的统一统一的潜在能量功能。主要目标是预测所有主要结构类别（Alpha，beta，Alpha+beta和Alpha/beta）的蛋白质的结构，其链长在4-6 Angstrom均方根均方根偏移范围内仅基于势能的全局优化。这将通过改善单个能量组件的功能形式和参数来实现，并通过优化总能量函数以反映部分展开结构的能量层次结构来确保电势的折叠特性。理解物理相互作用在蛋白质天然结构形成中的作用不仅可以使我们仅基于氨基酸序列的知识来预测蛋白质的最终结构，而且可以用于研究蛋白质折叠或错误折叠过程。预测蛋白质的三维结构或预测其折叠途径的能力可以极大地有助于针对癌症，阿尔茨海默氏症或prion脱舌的合理药物设计。