Exploring Ligand Binding Energy Landscape and Quantifying Specificity of Biomolecular Recognition

探索配体结合能量景观并量化生物分子识别的特异性

• 批准号: 0947767
• 负责人: Jin Wang
• 金额: $ 89.14万
• 依托单位: SUNY at Stony Brook
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0947767&HistoricalAwards=false
• 关键词: Exploring; Ligand; Binding; Energy; Landscape

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.

生物功能包括从分子到基因到器官的高度特异性。了解生物特异性对了解生物功能至关重要。本项目旨在为研究生物功能特异性寻找一个理论指导原则和统一框架。这个项目的方法有三个方面。首先，将开发一个配体结合能景观框架，以揭示和量化生物分子特异性。这将导致以一种基于基本物理原理的统一方式量化内在特异性。这种方法以前是不可能系统地完成的。配体结合能图谱的应用构成了从传统特异性到内在特异性思维的转变。其次，由于特异性是分子识别的一个重要方面，这种高特异性的分子识别标准可以作为一种优化方案。该优化方案将应用于生物分子结合自由能估计，这对理解亲和性和特异性至关重要。第三，探索结合亲和力和特异性对生物分子识别和功能进行二维表征的可能性，而不是传统的仅通过亲和力进行表征。体外和体内研究将与其他实验研究人员密切合作，以测试对信号转导过程和功能至关重要的Cox-2和Ras蛋白的生物靶向系统的特异性框架。本项目的主要智力优势在于，可以通过开发配体结合能景观框架和量化内在特异性来理解生物分子识别特异性重大挑战问题的原理和机制。所学习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，同时具有亲和力和特异性。该建议的更广泛影响是本文开发的方法在配体筛选和工程设计方面的潜在应用，以实现和增强特定的生物功能。该提案的教育方面将通过设计和引入新的计算生物学项目、理论生物物理/生物物理化学课程、生物物理系列研讨会和合作研究培训，将对生物学、化学和物理界面的学生和博士后产生广泛的影响。