Theory of Biomolecular Structure and Dynamics

拟议工作的目标是发展理论和 计算方法，可以用来解释的行为， 生物分子，并应用这些方法来帮助解释 各种生物学感兴趣的特定系统的活性。 一 第一个领域的主要重点将是统计和 机械和分子动力学模拟技术， 计算方法预测自由能变化与 分子组成和几何形状的同时变化。 等 方法应该是非常有用的预测如何配体结合 亲和力和化学反应速率随着分子的变化而变化， 组成，例如，拟议的工作包括发展 旨在使这两种预测实用的研究。 的 新的计算方法将被用来提供准确和详细的 胰蛋白酶分子识别的性质及其 突变体，在L-阿拉伯糖结合蛋白中，在抗体中，以及在 小核糖核酸病毒。 此外，用于模拟活化过程的方法将 用于研究溶剂对构象动力学的影响 不同蛋白质中的转换和配体结合。 这一工作将为药物、酶的设计提供有用的新工具 和其他分子的实际应用，并深化 了解生物分子的活动。 这项建议是由生物物理学计划，物理 化学项目和生物仪器项目等 三个计划将参与资助这项研究计划。

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.