Development and Application of Generalized Ensemble Algorithms for Protein Studies

蛋白质研究广义集成算法的开发与应用

• 批准号: 0313618
• 负责人: Ulrich Hansmann
• 金额: $ 32.8万
• 依托单位: Michigan Technological University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0313618&HistoricalAwards=false
• 关键词: Development; Application; Generalized; Ensemble; Algorithms

Professor Ulrich Hansmann is supported by the Theoretical Chemistry and Molecular Biophysics Programs to develop, distribute and apply generalized ensemble algorithms to the study of proteins. A primary emphasis of this work is on complicated methodological developments and subsequent export of resulting methodologies to other groups interested in large-scale simulation of biological processes. Specifically, Hansmann develops new means for computationally enhancing the frequency of transitions between interesting low-energy states. In addition, observed transitions are analyzed to determine chemically relevant reaction coordinates. Motivation is based on the need to increase simulation efficiency by an order of magnitude. This will be accomplished by inclusion of advanced physical concepts. In addition, an accurate means for accounting for solvent-solute interactions is being developed. Applications concentrate on investigating relative stabilities of and transitions between the helical and sheet-like structures of the b-amyloid peptide. Formation and aggregation of the sheet-like structures is a feature that is common to a number of neurological diseases.Proteins are a common yet important class of molecules in living systems. As enzymes, proteins catalyze and regulate a cell's biochemical reactions. As antibodies they contribute to the immune system. Since such functions are closely related to their three-dimensional shapes, small defects can cause misfolding which can cause a variety of diseases. Understanding these effects from computer simulation requires additional levels of complexity in both the theoretical models and in the computational approach employed to investigate the manifestations of the models. In addition to addressing the theoretical and computational issues for biochemical simulation, this work concentrates on understanding how misfolded structures of the b-amyloid peptide form and aggregate. The occurrence of such abnormal structures has been associated with Alzheimer's disease.

乌尔里希·汉斯曼教授得到了理论化学和分子生物物理学项目的支持，开发、分发和应用广义集成算法来研究蛋白质。这项工作的主要重点是复杂的方法学发展，以及随后将由此产生的方法学输出给对大规模生物过程模拟感兴趣的其他小组。具体地说，汉斯曼开发了一种新的方法，用于通过计算提高有趣的低能状态之间的转换频率。此外，还分析了观察到的转变，以确定化学上相关的反应坐标。动机是基于将模拟效率提高一个数量级的需要。这将通过包含先进的物理概念来实现。此外，正在开发一种计算溶剂-溶质相互作用的准确方法。应用集中于研究b-淀粉样肽螺旋结构和片状结构之间的相对稳定性和过渡性。片状结构的形成和聚集是许多神经系统疾病的共同特征。蛋白质是生命系统中一类常见但重要的分子。作为酶，蛋白质催化和调节细胞的生化反应。作为抗体，它们对免疫系统有贡献。由于这些功能与它们的三维形状密切相关，微小的缺陷可能会导致错误折叠，从而导致各种疾病。要从计算机模拟中理解这些影响，需要在理论模型和用于研究模型表现的计算方法中增加更多的复杂性。除了解决生化模拟的理论和计算问题外，这项工作还集中在了解b-淀粉样肽的错误折叠结构如何形成和聚集。这种异常结构的出现与阿尔茨海默病有关。