Collaborative Research: Improved Boundary Element Methods for Electrostatics of Interacting Proteins in Solvent

蛋白质分子是所有生命形式的基本组成部分，而静电效应在决定蛋白质结构和功能方面起着关键作用。然而，在实验上研究这些影响是困难的，人们对使用计算机模拟来推进这一生化研究领域非常感兴趣。该项目将通过开发新的数学算法来提高这些模拟的准确性和效率。潜在的生物医学应用包括(1)蛋白质-配体结合，这对合成药物设计很重要；(2)蛋白质折叠，这对了解错误折叠如何导致疾病很重要。研究人员将与生物科学家合作，在该项目中开发的软件将以开源格式提供给科学界使用。项目成果将通过会议和研讨会报告以及在科学期刊上发表文章来传播。该项目将通过培训博士后、研究生和本科生水平的初级人员来发展全国计算数学领域的劳动力。带电粒子系统的生物化学模拟通常受到计算远程静电相互作用的成本的限制。为了解决这个问题，PI开发了一种树形编码加速边界积分(TABI)方法来求解溶解蛋白质的静电势的泊松-玻尔兹曼(PB)方程。在这个项目中，PI将把TABI解算器扩展到具有挑战性的蛋白质在溶剂中相互作用的情况，专注于微妙的介电和离子结构效应。这项工作在建模、改进树编码和边界元方法以及在分子生物化学中的应用方面取得了进展，包括以下主题：(1)Tabi代码将被扩展到计算溶剂化蛋白质-蛋白质复合体的结合能。(2)树编码将用于加速参考相互作用位置模型(RISM)中总关联函数的计算，该模型提供了对溶质/溶剂界面附近的水结构的物理准确描述。(3)用显式离子模拟来验证PB和RISM模拟，并研究有限离子尺寸对界面电荷结构的影响。(4)将通过实施更有效的多极接受标准来改进树代码，并将开发树代码的并行CPU和GPU实现。(5)一种计算静电PB力的新方法将被应用于蛋白质在溶剂中相互作用的分子动力学模拟。(6)将使用TABI演示有效计算溶剂化蛋白质中的pH依赖效应。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Protein molecules are basic components in all forms of life, and electrostatic effects play a key role in determining protein structure and function. However studying these effects experimentally is difficult, and there is great interest in using computer simulations to advance this area of biochemical research. This project will contribute by developing new mathematical algorithms to improve the accuracy and efficiency of these simulations. Potential biomedical applications include (1) protein-ligand binding, which is important for synthetic drug design, and (2) protein folding, which is important for understanding how misfolding causes disease. The investigators will collaborate with bioscientists, and the software developed in the project will be made available in open source format for use by the scientific community. The project results will be disseminated through conference and seminar presentations, and publications in scientific journals. The project will develop the national workforce in computational mathematics by training junior personnel at the postdoctoral, graduate student, and undergraduate student levels. Biochemical simulations of charged particle systems are often limited by the cost of computing long-range electrostatic interactions. To address this issue the PIs have developed a treecode-accelerated boundary integral (TABI) method to solve the Poisson-Boltzmann (PB) equation for the electrostatic potential of a solvated protein. In this project the PIs will extend the TABI solver to the challenging case of interacting proteins in solvent, focusing on subtle dielectric and ionic structural effects. The work entails advances in modeling, improvements in treecode and boundary element methods, and applications in molecular biochemistry including the following topics: (1) The TABI code will be extended to compute the binding energy of a solvated protein-protein complex. (2) The treecode will be adapted to accelerate computations of the total correlation function in the Reference Interaction Site Model (RISM) which provides a physically accurate description of the water structure near the solute/solvent interface. (3) Explicit ion simulations will be carried out to validate the PB and RISM simulations, and to investigate the effect of finite ion size on the interfacial charge structure. (4) The treecode will be improved by implementing a more effective multipole acceptance criterion, and parallel CPU and GPU implementations of the treecode will be developed. (5) A new method for computing electrostatic PB forces will be tested for application in molecular dynamics simulations of interacting proteins in solvent. (6) Efficient computation of pH-dependent effects in solvated proteins will be demonstrated using TABI.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.