Theory of Biomolecular Structure and Dynamics

这项拟议工作的目标是开发可用于解释生物分子行为的理论和计算方法，并应用这些方法来帮助解释各种生物感兴趣的特定系统的活动。第一个领域的一个主要焦点将是结合统计力学和分子动力学模拟技术来产生预测与分子组成和几何结构同时变化相关的自由能变化的计算方法。例如，这种方法对于预测配体结合亲和力和化学反应速率如何随着分子组成的变化而变化非常有用，拟议的工作包括旨在使这两种预测变得实用的发展研究。新的计算方法将被用来准确和详细地描述胰酶及其突变体、L阿拉伯糖结合蛋白、抗体和小核糖核酸病毒的分子识别性质。此外，还将使用模拟激活过程的方法来研究溶剂对不同蛋白质中构象转变和配体结合动力学的影响。这项工作将为设计用于实际应用的药物、酶和其他分子提供有用的新工具，并加深对生物分子活性的了解。这项提议由生物物理计划、物理化学计划和生物仪器计划联合审查，所有三个计划都将参与这一研究项目的资助。

The objectives of the proposed work are to develop theoretical and computational methods that can be used to interpret the behavior of biological molecules, and to apply these methods to help explain the activity of a variety of specific systems of biological interest. A major focus in the first area will be the combination of statistical mechanical and molecular dynamics simulation techniques to produce computational methods for predicting free energy changes associated with the simultaneous variation of molecular composition and geometry. Such methods should be very useful for predicting how ligand-binding affinities and chemical reaction rates change with changes in molecular composition, for example, and the proposed work includes developmental studies aimed at making both these kinds of predictions practical. The new computational methods will be used to provide accurate and detailed descriptions of the nature of molecular recognition in trypsin and its mutants, in L-arabinose-binding protein, in antibodies, and in picornaviruses. Also, methods for simulating activated processes will be used to study solvent effects on the dynamics of conformational transitions and ligand binding in different proteins. This work should provide useful new tools for designing drug, enzymes and other molecules for practical applications, and the deepening of understanding of the activity of biological molecules. This proposal was jointly review by the Biophysics Program, the Physical Chemistry Program and the Biological Instrumentation Program and all three programs will participate in the funding of this research project.