Exploring Ligand Binding Energy Landscape and Quantifying Specificity of Biomolecular Recognition

生物功能包括从分子到基因到器官的高度特异性。了解生物特异性对于了解生物功能至关重要。该项目旨在为研究生物功能的特异性找到理论指导原则和统一框架。该项目的方法有三个方面。首先，将开发一个用于揭示和量化生物分子特异性的配体结合能景观框架。这将导致以基于基本物理原理的统一方式量化内在特异性。这种方法以前不可能系统地实现。配体结合能景观的应用构成了从传统特异性到内在特异性的思维转变。第二，由于特异性是分子识别的一个整体方面，因此分子识别的这种高特异性标准可以用作优化方案。这种优化方案将被应用到生物分子结合自由能估计理解亲和力和特异性至关重要。第三，将进行探索，以保持与二维表征的生物分子识别和功能的可能性与亲和力和特异性，而不是传统的表征与亲和力单独。将与其他实验研究人员密切合作进行体外和体内研究，以测试考克斯-2和Ras蛋白生物靶向系统的特异性框架，这对信号转导过程和功能至关重要。该项目的主要智力价值在于，通过开发配体结合能景观框架和量化内在特异性，可以理解生物分子识别特异性中重大挑战问题的原理和机制。所获得的原理可用于开发结合特异性的优化方法，并定量表征生物分子识别和功能的亲和力和特异性。更广泛的影响，这一建议是潜在的应用，这里开发的配体筛选和工程设计，实现和增强特定的生物功能的方法。该提案的教育方面将对生物学，化学和物理学接口的学生和博士后产生广泛影响，通过设计和引入新的计算生物学计划，理论生物物理学/生物物理化学课程，生物物理学系列研讨会和合作研究培训的研究和教育整合。

Biological function encompasses a high degree of specificity, from molecules to genes to organs. Understanding biological specificity is vitally important for understanding biological function. This project is aimed at finding a theoretical guiding principle and a unified framework for investigating the specificity of biological function. The approaches to the project are threefold. First, a ligand binding energy landscape framework to uncover and quantify biological molecular specificity will be developed. This will lead to the quantification of intrinsic specificity in a unified way based on the underlying physical principles. This approach could not have been accomplished systematically before. The application of a ligand binding energy landscape constitutes a shift of thinking from conventional specificity to intrinsic specificity. Second, since specificity is an integral aspect of molecular recognition, this high specificity criterion for molecular recognition can serve as an optimization scheme. This optimization scheme will be applied to bio-molecular binding free energy estimates crucial for understanding affinity and specificity. Third, explorations will be carried out in keeping with the possibility of two-dimensional characterization of biomolecular recognition and function with both affinity and specificity instead of conventional characterization with affinity alone. In vitro and in vivo studies will be performed in close collaboration with other experimental researchers, to test the framework of specificity on biological targeting systems of Cox-2 and Ras proteins, crucial for signal transduction process and function. The major intellectual merit of this project is that the understanding of the principles and mechanisms of grand challenge problems in bio-molecular recognition specificity can be achieved through the development of a ligand binding energy landscape framework and quantification of intrinsic specificity. The principles learned can be used to develop optimization method for binding specificity, and quantitatively characterize biomolecular recognition and function with both affinity and specificity. The broader impacts of this proposal are the potential applications of the methods developed here to the ligand screening and engineering design for realizing and enhancing specific biological function. The educational aspects of the proposal will have broad impact on students and post doctorals at the interface of biology, chemistry and physics, through the integration of research and education in designing and introducing a new computational biology program, a theoretical biological physics/biophysical chemistry course, a biological physics seminar series and collaborative research training.