Conceptual Aspects of the Protein Folding Problem

描述（由申请人提供）：提议的工作进一步发展了蛋白质折叠动力学和结构预测的统计能量景观方法。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，重点是局部挫折的作用；2)阐明膜蛋白的体外和体内折叠机制，提高我们预测其结构的能力。能量景观理论提供了用概率术语描述部分折叠蛋白质构型的能量集合和它们之间相互转换的动力学的数学技术。我们将使用分析和计算机模拟方法，为最小挫折相互作用网络在引导蛋白质进入其天然状态中的作用以及挫折在阻碍该流动中的作用提供定量估计。预计变构蛋白会积极地利用挫折来塑造功能景观。变构蛋白（如激酶）的突变可导致蛋白质致癌。膜蛋白折叠的错误会特别导致囊性纤维化等疾病。了解膜蛋白结构的进展有助于预测其结构，这是设计药物的重要一步。小灵通398/2590 （Rev. 11/07）页延续格式页

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