Conceptual Aspects of the Protein Folding Problem

蛋白质折叠问题的概念方面

• 批准号: 8274868
• 负责人: Peter Guy Wolynes
• 金额: $ 29.57万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274868
• 关键词: Accounting; Affect; Algorithms; Biological; Cells; Cereals; Collaborations; Computer Simulation; Coupled; Coupling; Cystic Fibrosis; Data; Defect; Disease; Drug Delivery Systems; Drug Design; Equilibrium; Evolution; Free Energy; Frustration; Genome; Genomics; Globular Protein Foldings; Health; In Vitro; Kinetics; Lead; Ligand Binding; Mediating; Membrane; Membrane Proteins; Modeling; Motion; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Oncogenic; Organism; Phase; Phosphotransferases; Post-Translational Protein Processing; Principal Investigator; Process; Protein Dynamics; Protein Region; Proteins; Role; Structure; Surveys; Techniques; Translating; Transport Process; Water; Work; base; conformational conversion; globular protein; improved; in vivo; programs; protein folding; protein misfolding; protein structure; simulation; theories; tool

DESCRIPTION (provided by applicant): The proposed work develops further the statistical energy landscape approach to protein folding dynamics and structural prediction. The specific aims are: 1) to elucidate coupling of the folding and functional energy landscapes of allosteric proteins, concentrating on the role of local frustration 2) to elucidate the mechanism of in vitro and in vivo folding of membrane proteins and to improve our ability to predict their structure. Energy landscape theory provides mathematical techniques for characterizing in probabilistic terms the energies of the ensembles of partially folded protein configurations and the dynamics of interconverting between them. We will use analytical and computer simulation approaches that will provide quantitative estimates for the role of minimally frustrated networks of interactions in guiding the protein to its native state and the role that frustration has in impeding that flow. Allosteric proteins are predicted to positively use frustration to sculpt the functional landscape. Mutation in allosteric proteins such as kinases can cause a protein to be oncogenic. Errors in the folding of membrane proteins can lead specifically to diseases such as cystic fibrosis. Advances in understanding the landscape of membrane protein can help predict their structure an important step in designing drugs. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Folding is a key step in translating genomic data into function. Our work on the energy landscape theory of folding helps predict protein structures of drug targets. The elucidation of folding mechanism is also important for understanding diseases caused by errors in folding, such as cystic fibrosis and Type II diabetes. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

描述（由申请人提供）：拟议的工作进一步开发了蛋白质折叠动力学和结构预测的统计能量格局方法。具体目的是：1）阐明变构蛋白的折叠和功能能量景观的耦合，集中在局部挫败感上2）阐明体外和体内膜蛋白的折叠机制，并提高我们预测其结构的能力。能量景观理论提供了数学技术，用于用概率术语表征部分折叠蛋白构型的合奏的能量以及它们之间相互转化的动力学。我们将使用分析和计算机仿真方法，这些方法将提供定量估计，以估算最小沮丧的相互作用网络在将蛋白质引导到其本地状态以及挫败感在阻碍该流动方面的作用。预测变构蛋白会积极地使用挫败感来雕刻功能景观。变构蛋白（例如激酶）的突变会导致蛋白质致癌。膜蛋白折叠中的错误可能会导致诸如囊性纤维化之类的疾病。了解膜蛋白的景观的进步可以帮助预测其结构在设计药物方面的重要一步。 PHS 398/2590（Rev. 11/07）页面延续格式页面 公共卫生相关性：折叠是将基因组数据转化为功能的关键步骤。我们对折叠能量景观理论的工作有助于预测药物靶标的蛋白质结构。释放机制的阐明对于理解折叠错误引起的疾病（例如囊性纤维化和II型糖尿病）也很重要。 PHS 398/2590（Rev. 11/07）页面延续格式页面