EAGER: Free Energy Sampling of Biomolecular Dynamics at Biological Timescales

佛罗里达州立大学的杨伟（音译）在化学系化学理论、模型和计算方法项目的支持下，在生物时间尺度上研究生物分子系统。蛋白质折叠通常发生在几百微秒到几毫秒甚至几秒钟的时间尺度上。这个范围对传统的计算机模拟方法提出了挑战，传统的计算机模拟方法试图提供长时间尺度变化的定量描述。到目前为止，只有少数几个计算达到了一毫秒的时间尺度。由于缺乏适当的计算方法，这些计算受到了阻碍。杨教授通过在他的计算方法中提供严格的、物理驱动的机制来应对这一挑战。这项研究的结果可能会提高我们在生物时间尺度上对生物分子运动进行实际采样的能力。这些时间尺度与生物化学和生物物理过程相关，如蛋白质折叠（在阿尔茨海默病和其他疾病中很重要）和药物设计。新的算法和代码正在通过社区平台传播。研究人员还在佛罗里达州立大学举办了一年一度的研讨会。计算方法可用于制药工业发现新的药物结合位点和新的治疗人类健康。这个项目有可能促进社会的健康和福利。该项目通过实现对杨教授的正交空间采样（OSS）框架和算法进行定性扩展的新发展，解决了生物分子动力学自由能采样的瓶颈“隐藏障碍”挑战。该项目的具体目标包括开发一种自适应策略，以便在模拟过程中动态修改OSS哈密顿量和相关的偏置势。研究小组还实现了高阶偏置函数，其中高阶偏置项可以在链式关系中加速能量流向下一个低阶项。这两种策略都旨在改善环境（正交空间）与系统自然集体坐标之间的动态耦合和能量流动，并使全局结构松弛与集体坐标的演化同步。新方法正在通过应用于长期尺度的蛋白质构象动力学来评估，这些蛋白质具有重要的生物学意义，包括腺苷酸激酶，β -2-肾上腺素能受体；HIV蛋白酶;还有人类葡萄糖激酶。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。

Wei Yang of Florida State University is supported by the Chemical Theory, Models and Computational Methods Program in the Division of Chemistry to study biomolecular systems at biological timescales. Protein folding commonly occurs at timescales ranging from hundreds of microseconds to milliseconds and even seconds. This range presents a challenge to conventional computer simulation methods that seek to provide a quantitative description of changes on a long timescale. Only a few calculations of up to the one millisecond timescale have been reported to date. These calculations have been hindered by the lack of appropriate computational methods. Professor Yang is addressing this challenge by providing rigorous, physically-motivated mechanisms in his computational methods. The outcome of this research may improve our ability to perform practical sampling of biomolecular motions at biological timescales. These timescales have relevance in biochemical and biophysical processes such as protein folding (important in Alzheimer's disease and others) and pharmaceutical drug design. The new algorithms and codes are being disseminated through community-based platforms. The researchers are also holding an annual workshop hosted at Florida State University. The computational methods may be used by the pharmaceutical industry to discover new drug binding sites and new treatments for human health. This project has the potential to advance the health and welfare of society.This project is addressing the "hidden barrier" challenge that has been the bottleneck for free energy sampling of biomolecular dynamics, by realizing novel developments that qualitatively extend Professor Yang's orthogonal space sampling (OSS) framework and algorithms. Specific aims of this project include the development of an adaptive strategy to dynamically modify the OSS Hamiltonian and associated biasing potentials during the course of a simulation. The research group also implements higher-order biasing functions, where a higher-order biasing term can accelerate energy flow to the next lower order term in a chained relationship. Both strategies are designed to improve dynamical coupling and energy flow between the environment (orthogonal space) and the natural collective coordinate of the system, and synchronize global structural relaxation with the evolution of the collective coordinate. The new methodology is being assessed through applications to long-timescale protein conformational dynamics for biologically-important proteins that have been experimentally characterized, including adenylate kinase, beta-2-adrenergic receptor; HIV protease; and human glucokinase.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.