Classical MD with Mobile Protons, with Applications to Membrane Proteins

该项目的目标是在经典分子动力学计算机模拟中使质子在适当的化学基团之间运动-这种方法允许计算蛋白质结构。这种质子运动在许多生化过程中都很重要，比如蛋白质的pH滴定、酶催化、质子通道、质子泵、转运体和细胞的“能量货币”ATP的合成。质子的运动涉及到共价键的断裂和形成，而经典的模拟通常无法提供这一点。这项研究将由本科生、研究生和博士后在一个学生多样性显著的机构进行（53%的学生属于代表性不足的群体）。本项目开发的方法将通过流行的计算机软件包（如CHARMM）提供给研究界。这个项目包括方法开发和生物学问题的调查。基础将是最近开发的混合分子动力学/蒙特卡罗算法，该算法允许质子在氢键伙伴之间以适度的计算成本移动。该算法将被进一步开发、改进和测试，以确保在任何环境下都有适当的动力学和热力学，并扩展其对生物系统的适用性。它将借鉴一些最先进的方法来处理长时间尺度，并增加它自己对质子转移的特定贡献。它有望促进对涉及质子运动的关键生物过程的更好理解。第一个被研究的生物系统包括流感病毒的M2质子通道和人类Hv1质子通道。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The goal of this project is to enable proton movement between appropriate chemical groups in classical molecular dynamics computer simulations - methodology which allows calculation of proteins structures. This proton movement is important in a multitude of biochemical processes, such as pH titration of proteins, enzyme catalysis, proton channels, proton pumps, transporters, and the synthesis of ATP, the 'energy currency' of cells. Proton movement involves breaking and formation of covalent bonds, and classical simulations are normally not equipped to provide for this. This research will be carried out by undergraduate, graduate, and postdoctoral students at an institution with remarkable student diversity (53% of the students belong to underrepresented groups). The methods developed in this project will be made available to the research community through popular computer packages such as CHARMM.This project includes both method development and investigation of biological questions. The basis will be a recently developed hybrid Molecular Dynamics/Monte Carlo algorithm that allows proton movement between hydrogen-bonded partners at modest computational cost. This algorithm will be further developed, improved, and tested to ensure proper kinetics and thermodynamics in any environment and to extend its applicability to biological systems. It will draw from a number of state-of-the art methodologies for dealing with long time scales, adding its own contributions that are specific to proton transfer. It is expected to facilitate the better understanding of key biological processes that involve proton movement. The first biological systems to be studied include the M2 proton channel of the influenza virus and the Hv1 human proton channel.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.