Hybrid Computational Modeling and Advanced Numerical Methods for Biomolecular Interactions

生物分子相互作用的混合计算模型和高级数值方法

• 批准号: 2208465
• 负责人: Li-Tien Cheng
• 金额: $ 53.69万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2208465&HistoricalAwards=false
• 关键词: Hybrid; Computational; Modeling; Advanced; Numerical

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 serves 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 complex problem of molecular association and dissociation, the investigators will 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 basic research in scientific computing and numerical analysis, particularly at the interface of dynamics and stochastic modeling. This research will 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.

该项目开发严格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解离的主要机制。通常，药物分子在拥挤的环境中移动，并找到蛋白质表面的一个点来结合，停留在那里，也可以离开，与蛋白质解除结合。在这种经常重复的结合和解除结合事件期间，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，特别是水分子相互作用。这种以多重时空尺度和多体效应为特征的复杂过程存在两个关键的科学问题。一是药物-蛋白质结合单元的稳定性。这种热力学稳定性可以作为寻找能够与目标蛋白质结合的药物分子的标准。另一个是绑定和解除绑定发生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于药物的有效性和功效至关重要。几十年来，科学界在寻找这些问题的定量答案以指导计算机辅助药物设计和发现方面取得了巨大的成果。然而，美国国立卫生研究院最近对现有此类计算机程序的评估得出的结论是，迫切需要先进的科学理论来改进实践。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，有可能有助于降低实验室实验通常所需的高昂成本，并加快药物发现的进程。此外，这个高度跨学科的研究项目为不同层次的学生提供了接受数学、计算和生物科学接口培训的独特机会，从而在竞争激烈的国际环境中保持我国的科学研究实力。为了解决分子缔合和解离的复杂问题，研究人员将设计、实现和分析一种非常快速的界面弛豫二元水平集方法，以捕获分子界面结构。 先进的变分分子溶剂化理论。新方法结合了阈值动力学和二进制水平集表示的强度，并利用底层能量景观的局部性和新的像素翻转技术，以实现非常高的效率。 他们还开发了一种新的界面随机动力学的混合计算方法，通过快速算法耦合界面能量最小化、过渡路径的弦方法以及新颖的多状态布朗动力学模拟。所有这些都专门用于研究分子结合和解离动力学，而一些传统方法（例如标准布朗动力学模拟）可能会失败。预计该项目将显着推进科学计算和数值分析方面的基础研究，特别是在动力学和随机建模领域。这项研究将有助于解决解决非常复杂的科学问题的一些瓶颈问题。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Explicit-solute implicit-solvent molecular simulation with binary level-set, adaptive-mobility, and GPU

• DOI: 10.1016/j.jcp.2022.111673
• 发表时间: 2022-10-18
• 期刊: JOURNAL OF COMPUTATIONAL PHYSICS
• 影响因子: 4.1
• 作者: Liu，Shuang;Zhang，Zirui;Li，Bo
• 通讯作者: Li，Bo