CONCEPTUAL ASPECTS OF THE PROTEIN FOLDING PROBLEM

拟议的工作探索使用能源景观的想法来研究 蛋白质折叠问题。具体目标是(1)将能量量化 蛋白质的景观，特别是描述中等程度的 在部分折叠的蛋白质中进行排序(2)以开发新的描述 蛋白质折叠的动力学，以帮助规划和 解释新的折叠快速动力学实验，以及(3) 开发用于预测蛋白质结构的新算法 序列信息并将这些算法应用于重要目标， 尤其是类固醇激素的激素结合区 感受器。能源景观理念是一种数学技术 用统计术语来刻画 蛋白质的构型，并研究蛋白质如何被引导到它的 起作用的折叠状态。除了分析方法，新的 提出了计算机模拟技术来预测结构和 表现出朝向原生状态的主导流动的特征。的研究。 部分折叠的蛋白质和折叠结构的途径是直接的 健康利益，因为错误折叠的蛋白质与几个人类 疾病，包括阿尔茨海默氏症。改进的算法，用于 结构预测有助于加快基于结构的药物设计。我们的 关注荷尔蒙受体是因为它们在乳房中的重要性 前列腺癌、甲状腺疾病和发育障碍。

The proposed work explores the use of energy landscape ideas to study the protein folding problem. The specific aims are (1) to quantify the energy landscape of proteins especially to characterize intermediate degrees of order in partially folded proteins (2) to develop new descriptions of the kinetics of protein folding, so as to assist in the planning and interpretation of new fast kinetics experiments for folding, and (3) to develop new algorithms for the prediction of protein structure using sequence information and to apply these algorithms to important targets, in particular, the hormone binding regions of the steroid hormone receptors. Energy landscape ideas are mathematical techniques for characterizing in statistical terms the energies of the ensemble of configurations of a protein and to study how a protein is guided to its functioning folded states. In addition to analytical approaches, new computer simulation techniques are proposed for predicting structure and characterizing the dominant flow toward the native state. The study of partially folded proteins and the route to folded structures is of direct health interest because misfolded proteins are involved in several human diseases, including Alzheimer's disease. Improved algorithms for structure prediction help in speeding up structure based drug design. Our focus on the hormone receptors is motivated by their importance in breast and prostate cancer, thyroid disease and in disorders of development.