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)阐明蛋白质能量景观地形的分子起源，强调溶剂和侧链自由度的作用；2)阐明折叠动力学屏障和蛋白质亚稳态的微观起源；3)进一步发展基于严格的统计力学算法，用于考虑溶剂和侧链自由度的结构预测。能量景观理论提供了数学技术，用概率术语来描述部分折叠蛋白质结构的能量集合和它们之间相互转换的动力学。分析和计算机模拟两种方法都被提出，将提供定量估计单个氨基酸在引导蛋白质进入其天然状态和阻碍其流动方面所起的作用。折叠动力学的变化影响蛋白质运输，并被认为与许多疾病的发病有关，包括阿尔茨海默病、2型糖尿病和囊性纤维化。从序列中预测准确的三维蛋白质结构的能力的提高将在一般利用从人类和细菌基因组测序项目中获得的数据方面具有重要价值。

DESCRIPTION (provided by applicant: The proposed work develops further the statistical energy landscape approach to protein folding dynamics and structure prediction. The specific aims are: 1) to elucidate molecular origins of protein energy landscape topography, emphasizing the role of the solvent and side chain degrees of freedom; 2) to elucidate the microscopic origins of kinetic barriers to folding and of protein metastability; and 3) to further develop rigorously based statistical mechanical algorithm for structure prediction that account for solvent and side chain degrees of freedom. 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. Both analytical and computer simulation approaches are proposed that will provide quantitative estimates for the role individual amino acids play, both in guiding the protein to its native state, and in impeding that flow. Changes in folding kinetics affect protein trafficking and are thought to be involved in the pathogenisis of many diseases including Alzheimer's disease, Type II diabetes and cystic fibrosis. The improved ability to predict accurate three dimensional protein structures from sequence will be of great value in generally making use of data obtained from both human and bacterial genome sequencing projects.