CONCEPTUAL ASPECTS OF THE PROTEIN FOLDING PROBLEM

提出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)建立测量褶皱过程中景观能量景观的基本统计力学理论；2)预测和解释蛋白质折叠早期事件的结构方面；3)了解长时间尺度上折叠动力学屏障和蛋白质亚稳态的微观起源；4)进一步发展基于严格统计算法的蛋白质三级结构预测。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。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机制有关，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。

The proposed work develops further the statistical energy landscape approach to protein folding dynamics and structure prediction. The specific aims are: 1) to develop fundamental statistical mechanical theories for surveying the energy landscapes of landscapes during folding; 2) to predict and interpret the structural aspects of the early events in protein folding; 3) to understand the microscopic origin of kinetic barriers to folding on long time scales and of protein metastability; 4) to further develop rigorously based statistical algorithms for the prediction of protein tertiary 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. 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 pathogenesis 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.