Fast Algorithm for Interface Relaxation and Efficient Computational Modeling of Molecular Binding and Unbinding

该项目发展了严谨的科学理论和强大的计算工具来研究药物和蛋白质分子结合和分离的主要机制。通常，药物分子在拥挤的环境中四处移动，找到一个蛋白质表面的一个点来结合，停留在那里，也可以离开，与蛋白质分离。在这种经常重复的结合和解除结合的过程中，两个分子不断地改变其内部原子位置。它们还与周围环境中的其他分子相互作用，尤其是水分子。这种具有多时空尺度和多体效应特征的复杂过程有两个关键的科学问题。一个是药物-蛋白质结合单位的稳定性。这种热力学稳定性是寻找能够与目标蛋白结合的药物分子的标准。另一个是绑定和解除绑定的速度有多快或多慢。最近在实验和计算机模拟中发现，这种动力学对药物的有效性和疗效至关重要。几十年来，科学界通过寻找这些问题的定量答案来指导计算机辅助药物设计和发现，取得了巨大的成就。然而，美国国立卫生研究院（National Institutes of Health）最近对现有的此类计算机程序进行了评估，得出的结论是，迫切需要先进的科学理论来改进这种做法。因此，该项目的成功可以为药物设计和发现提供坚实的理论基础和计算算法，可能有助于降低实验室实验通常需要的非常高的成本，并加快药物发现的过程。此外，这个高度跨学科的研究项目为不同水平的学生提供了独特的机会，在数学、计算和生物科学的界面上接受训练，使我国在激烈竞争的国际环境中保持科学研究的实力。为了解决分子结合和解离的极端复杂问题，研究人员设计、实现并分析了一种非常快速的界面弛豫二元水平集方法，以在先进的变分分子溶剂化理论框架中捕获分子界面结构。该方法将阈值动态的强度与二值水平集表示相结合，并利用底层能量格局的局部性和新的像素翻转技术来实现非常高的效率。他们还开发了一种新的混合计算方法，用于界面随机动力学动力学，通过快速算法耦合界面能量最小化，转换路径的字符串方法，以及一种新的多态布朗动力学模拟。所有这些都是专门用于研究分子结合和解结合动力学的，对于这些动力学，一些传统的方法，如标准布朗动力学模拟可能会失败。预计该项目将对科学计算和数值分析的基础研究，特别是界面动力学和随机建模的基础研究起到重要的推动作用。如果成功，这项研究可以帮助解决一些瓶颈问题，解决非常复杂的科学问题。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。

This project develops rigorous scientific theories and powerful computational tools to investigate the principal mechanisms by which drug and protein molecules associate and dissociate. Often, a drug molecule moves around in a crowded environment, and finds a spot of the surface of a protein to bind to, stays there, and can also leave, unbinding from the protein. During such binding and unbinding events, often repeated, both molecules constantly change their internal atomic positions. They also interact with other molecules, particularly the water molecules, in the surrounding environment. There are two key scientific questions on such complex processes that are characterized by multiple spatiotemporal scales and many-body effects. One is how stable the drug-protein bound unit is. Such thermodynamic stability severs as a criterion for searching drug molecules capable of binding to targeted proteins. The other is how fast or slow the binding and unbinding can occur. Such kinetics has been found recently in experiments and computer simulations to be critical to the drug effectiveness and efficacy. For decades, the scientific communities have made an enormous amount of effect, searching the quantitative answers to these questions to guide the computer-aided drug design and discovery. A recent assessment by the National Institutes of Health of the existing such computer programs, however, has concluded that advanced scientific theories are needed urgently to improve the practice. The success of this project can therefore provide a solid theoretical foundation as well as computational algorithms for drug design and discovery, potentially helping reduce the very high cost often needed for laboratory experiments and speed up the process of drug discovery. In addition, this highly interdisciplinary research project provides unique opportunities for students at different levels to receive training at the interface of mathematical, computational, and biological sciences, keeping our nation's strength in scientific research in a highly competitive international environment.To tackle the extreme complex problem of molecular association and dissociation, the investigators design, implement, and analyze a very fast binary level-set method for interface relaxation to capture the molecular interfacial structures in the framework of an advanced, variational molecular solvation theory. The new method combines the strength of the threshold dynamics and the binary level-set representation, and utilizes the locality of the underlying energy landscape, and new pixel-flipping techniques to achieve very high efficiency. They also develop a new and hybrid computational approach to the kinetics of interface stochastic dynamics, coupling the interfacial energy minimization by the fast algorithm, the string method for transition pathways, and a novel, multi-state Brownian dynamics simulations. All these are applied specifically to investigating the molecular binding and unbinding kinetics for which, some of the conventional methods such as the standard Brownian dynamics simulations may fail. It is expected that this project will advance significantly the basic research in scientific computing and numerical analysis, particularly those of the interface dynamics and stochastic modeling. If successful, this research can help resolve some of the bottle-neck issues in solving very complex scientific problems.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.