CAREER: Understanding Biomolecular Recognition Involving Large Conformational Changes

分子识别是现代分子生物学的关键问题之一。虽然刚性和半刚性结合已被广泛探索，但在细胞的过程和功能中经常发现的具有大构象变化的柔性结合尚未得到很好的了解。该项目由分子和细胞生物科学部的分子生物物理学和化学部的理论和计算化学项目共同支持，目的是建立一个理论框架来理解基本机制（灵活性如何帮助识别）并量化柔性结合的动力学路径。柔性结合的研究将分三个步骤进行：首先，建立柔性结合的理论框架，了解柔性对热力学性质的作用。其次，将开发路径积分形式，以量化动力学结合路径，了解柔性和折叠在柔性结合动力学中的作用，并回答有关结合基本机制的问题，例如结合更有可能采取哪一组动力学路径。第三，探讨灵活性如何帮助原子水平的识别。本研究的主要智力价值在于通过发展新的理论框架和确定动力学路径来理解柔性生物分子识别的基本机制。所学习的原理可用于指导特定识别复合物的原子级动力学路径模拟，克服传统的计算瓶颈，探索动态函数。该项目的教育方面将对来自世界各地从事生物/化学/物理交叉学科研究的学生产生广泛影响，首先是美国、中国和巴西的学生。将把研究和教育工作结合起来。这包括为本科生和研究生设计跨学科课程和生物分子识别和计算生物学课程；写一本关于生物分子能量景观的书；将本研究中开发的方法与工业应用联系起来；开展国际（中国和巴西）生物分子识别合作研究和教育项目。

Molecular recognition is one of the key issues in modern molecular biology. Although rigid and semi-rigid binding has been extensively explored, flexible binding with large conformational changes which is often found in the process and function of the cell is not well understood yet. The objective of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences and the Theoretical and Computational Chemistry Program in the Chemistry Division, is to establish a theoretical framework to understand the fundamental mechanism (how flexibility might help recognition) and quantify the kinetic paths of the flexible binding. The study of the flexible binding will be carried out in three integrated steps: First, a theoretical framework for flexible binding will be established to understand the role of flexibility on the thermodynamic properties. Second, a path integral formalism will be developed to quantify the kinetic binding paths, understand the roles of flexibility and folding on the kinetics of flexible binding, and answer the questions on the fundamental mechanism of binding such as which set of kinetic paths the binding will be more likely to take. Third, the question of how the flexibility helps the recognition at the atomic level will be explored. The major intellectual merit of this research is to understand the fundamental mechanisms of flexible bio-molecular recognition through the development of a new theoretical framework and identification of kinetic paths. The principles learned can be used to guide the atomic level kinetic path simulations of specific recognition complexes, overcome the conventional computational bottleneck and explore the dynamic functions. The educational aspect of the project will have broad impact on students from all over the world pursuing interdisciplinary studies at the interface of biology/chemistry/physics, starting with the students in the U. S., China, and Brazil. The research and education efforts will be integrated. This includes designing interdisciplinary courses and curricula on bio-molecular recognition and computational biology for undergraduate and graduate students; writing a book on energy landscapes of bio-molecules; linking the methodologies developed in this research to applications in industry; and developing an international (China and Brazil) collaborative research and education program on bio-molecular recognition.