Modeling and Theory of Biomolecular Association

该奖项由2009年美国复苏和再投资法案(公法111-5)资助。配体和蛋白质的结合在生物学中具有基本的重要性，在免疫、新陈代谢、信号和认知等功能中发挥着不同的作用。布朗动力学和连续介质模拟方法的最新进展为研究生物分子体系中的扩散提供了强有力的工具，但它们大多局限于接近扩散控制一步缔合过程极限的体系。对于更复杂的过程，如涉及短程相互作用和配体和蛋白质构象变化的两步缔合过程，现有的方法可能不够可靠，无法研究缔合途径和预测速率常数。该项目将开发新的计算机模拟工具和理论模型来研究两步结合过程。这项工作将分三个步骤进行：第一，将布朗动力学模拟方法和连续介质模拟方法相结合，开发新的多尺度方法来研究配体-蛋白质相遇和缔合速率常数。其次，新代码将针对现场可编程门阵列(FGA)进行修改。值得注意的是，现场可编程门阵列是新的硬件代码加速器，可以极大地加速计算。第三，结合途径的自由能分布、势垒以及配体-受体结合和解离的动力学和热力学性质将由几个广泛使用的分子模拟软件包和即将开发的方法计算。该协会将把研究活动与不同层次的教育结合起来。青年科学家的培训，包括研究生、本科生以及博士后研究员，将是PI小组的中心重点。国际科学协会强烈鼓励来自科学方面代表性不足群体的本科生参与研究。当地高中生还将有机会通过国际和平研究所的各种项目在国际和平研究所的实验室获得研究经验。PI将分发在该项目中开发的所有代码。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).The association of ligand and protein is of fundamental importance in biology, playing roles in functions as diverse as immunity, metabolism, signaling, and cognition. Recent advances on Brownian dynamics and continuum simulation methods provide powerful tools to study diffusion in biomolecular systems, but they are mostly restricted to systems that are near the limit of diffusion-control one-step association processes. For more complicated processes, such as two-step association processes that involve short-range interactions and conformational changes of ligands and proteins, existing methods may not be reliable enough to study the association pathways and predict the rate constants. This project will develop new computer simulation tools and theoretical models to study the two-step binding processes. This work will be carried out in three integrated steps: First, new multi-scale methods, combining Brownian dynamics simulation methods and continuum simulation methods to study ligand-protein encounters and association rate constants will be developed. Second, the new codes will be modified for field programmable gate arrays (FPGAs). Notably, FPGAs are new hardware code accelerators that can largely speedup the calculations. Third, free energy profile of binding pathways, energy barriers and kinetic and thermodynamic properties of ligand-receptor association and dissociation will be computed by several widely used molecular simulation packages and methods to be developed. The PI will integrate the research activities with education at different levels. The training of young scientists, including graduate students, undergraduates, as well as postdoctoral fellows, will be a central focus of the PI's group. The PI strongly encourages undergraduates from underrepresented groups in science to participate in the research. Local high school students will also have the opportunity to gain research experience in the PI's lab through a variety of programs at the PI's institution. The PI will distribute all codes developed in this project.