Conceptual Aspects of the Protein Folding Problem

描述（由申请人提供：拟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。具体目标是：1）阐明蛋白质能量景观拓扑学的分子起源，强调溶剂和侧链自由度的作用; 2）阐明折叠动力学障碍和蛋白质亚稳定性的微观起源; 3）进一步开发基于严格统计力学算法的结构预测，解释溶剂和侧链自由度。能量景观理论提供了数学技术的特点，在概率方面，能量的合奏部分折叠蛋白质的配置和动力学之间的相互转换。分析和计算机模拟的方法提出，将提供定量估计的作用，个别氨基酸发挥，无论是在引导蛋白质的天然状态，并在阻碍流动。折叠动力学的变化影响蛋白质运输，并且被认为涉及许多疾病的发病机制，包括阿尔茨海默病、II型糖尿病和囊性纤维化。从序列预测准确的三维蛋白质结构的能力的提高将在通常利用从人类和细菌基因组测序计划获得的数据方面具有很大的价值。

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.