Improving the Accuracy of the Amber Force Field for Biomolecular Simulation

石溪大学(SBU)的卡洛斯·西默林(Carlos Simmerling)得到了化学部化学理论、模型和计算方法项目的支持，以开发改进的蛋白质分子计算模型。蛋白质是生物学的主力。它们在人类和所有其他生物体内发挥着20,000多种不同的化学和机械功能。理解生物学的详细机制的一个主要挑战是蛋白质不是刚性物体。它们以对其功能至关重要的方式移动和扭曲。这通常是分子之间关键的识别发生的地方，因为分子之间相互适应并拉着对方，以确认他们与正确的伴侣互动，就像两只手在握手时适应一样。这些关键的运动可以通过原子细节的计算机模拟来研究，使用被称为力场的基本量子力学力的经典近似。力场使蛋白质及其相互作用的精确模拟成为可能，即使在最大的超级计算机上，这些研究也是很难处理的。除了基础的生物学研究外，精确的力场对于药物发现和新型纳米级和仿生材料的设计也是必不可少的。Simmerling教授与布鲁克海文国家实验室的Qin Wu合作，正在对生物物理和生物分子系统的分子动力学模拟中最重要的模型之一--琥珀力场--进行全面、系统、基于物理的重塑。该项目的目标是显著提高力场的准确性和保真度，同时保持其长期模拟大型生物分子系统的能力。新参数化的力场将免费供模拟社区下载和使用，用于在XSEDE超级计算机和小型实验室集群上运行的最广泛使用的分子动力学模拟代码中。该项目的推广工作包括通过SBU包容性教育中心协调，定期前往HBCU机构进行研究和招聘，并从代表性不足的少数民族中招募本科生参与研究。该项目的目标是系统和一致地解决现有蛋白质经典力场的几个关键限制，以便在不大幅增加计算复杂性的情况下提高其准确性。目前的模型在某些情况下有效，但在许多其他情况下与实验不一致，包括定量复制氨基酸的特定性质，如螺旋倾向。Simmerling教授与布鲁克海文国家实验室的合作者秦武一起，正在开发更准确的蛋白质骨架结构和动力学的能量分布描述，具有更好的序列相关结构和动力学，以扩展和重新参数化琥珀力场。该项目有三个主要目标：(1)通过在溶液中使用高水平QM计算来适应多维扫描，改进对主干能量学的描述；(2)扩展琥珀力场参数库，以包括生物学中遇到的非标准氨基酸以及那些经常用作实验探针的氨基酸；以及(3)开始解决在处理短程van der Waals相互作用方面的长期弱点，方法是利用量子力学能量分解方法的最新进展来训练替代函数形式。这些都将提高模型再现已知的侧链旋转体对骨架构象偏好的影响的能力。新的力场模型正在通过广泛使用的琥珀分子动力学(MD)模拟程序进行验证、记录和分发，并且可以独立下载，以便与其他广泛使用的MD代码一起使用。教育和外展的重点是为SBU中代表性不足的群体的学生招募和提供实验室研究经验，并通过到HBCU机构的外展旅行来鼓励学生对科学和研究的兴趣。

Carlos Simmerling of Stony Brook University (SBU) is supported by an award from the Chemical Theory, Models and Computational Methods program in the Chemistry Division to develop improved computational models of protein molecules. Proteins are the workhorses of biology. They perform more than 20,000 different chemical and mechanical functions in humans, and in all other living organisms. A major challenge in understanding the detailed mechanisms of biology is that proteins are not rigid objects. They move and twist in ways that are essential for their function. This is often where the crucial recognition between molecules takes place, as molecules adapt and pull on each other to confirm that they are interacting with the correct partner, much as two hands adapt during a handshake. These crucial motions can be studied via atomically-detailed computer simulations, using classical approximations to the underlying quantum mechanical forces, known as force fields. Force fields enable the accurate simulation of proteins and their interactions, studies that would otherwise be intractable, even on the largest supercomputers. In addition to fundamental biological studies, accurate force fields are essential for drug discovery and the design of novel nanoscale and biomimetic materials. Professor Simmerling, in collaboration with Qin Wu of Brookhaven National Laboratory, is performing a comprehensive, systematic, physics-based reshaping of one of the most important models used in molecular dynamics simulations of biophysical and biomolecular systems, the Amber force field. The goal of the project is to significantly improve the force field's accuracy and fidelity, while preserving its ability to simulate large biomolecular systems for long times. The newly-parameterized force field will be made freely available for download and use by the simulation community, for use within the most widely-used molecular dynamics simulation codes running on XSEDE supercomputers and small lab clusters. Outreach efforts for the project include regular research and recruitment trips to HBCU institutions, coordinated through the SBU Center for Inclusive Education, and the recruitment of undergraduates from underrepresented minorities to participate in the research.The goal of this project is to systematically and consistently address several key limitations of existing protein classical force fields in order to improve their accuracy without dramatically increasing computational complexity. Current models work in some cases, but fail to agree with experiment in many others, including quantitative reproduction of amino-acid specific properties such as helical propensity. Professor Simmerling, in conjunction with collaborator Qin Wu of Brookhaven National Laboratory, is developing more accurate descriptions of the energy profiles for protein backbone structure and dynamics, with better sequence-dependent structure and dynamics, in order to extend and reparameterize the Amber force field. The project has three principal aims: (1) to improve the description of backbone energetics through fitting to multidimensional scans using high-level QM calculations in solution, (2) to expand the Amber force field parameter library to include non-standard amino acids encountered in biology and those frequently used as experimental probes, and (3) to begin to address longstanding weaknesses in the treatment of short-range van der Waals interactions, by taking advantage of recent advances in quantum mechanical energy decomposition methods to train alternate functional forms. These should improve the ability of the model to reproduce the known influence of side chain rotamer on backbone conformational preference. The new force field models are being validated, documented, and distributed via the widely-used Amber molecular dynamics (MD) simulation program, and can be independently downloaded for use in conjunction with other widely-used MD codes. Education and outreach is focused on recruiting and providing lab research experiences for students from underrepresented groups at SBU, and encouraging student interest in science and research through outreach trips to HBCU institutions.