Collaborative Research: Implicit Solvent Modeling and Fast Algorithm Development for Simulating Solutes with Atomic Polarizable Multipoles

这一合作研究项目旨在改进隐式溶剂模型，以研究蛋白质、DNA和RNA等溶质与其周围溶剂环境之间的静电相互作用。这项研究将改进现有的方法，并将建立一个新的具有改进和提高建模精度的可极化多极隐式溶剂模型。此外，还将开发高效和准确的数值算法来满足新模型的计算挑战。这项研究将为生物物理学家提供一种新的工具，用于分析溶剂化生物分子的静电相互作用，其形式是在免费提供的软件包中实现的模型和算法。此外，该项目将为本科生和研究生提供生物建模、计算和数学分析方面的跨学科研究和培训机会。该项目将解决现有隐含溶剂模型在研究溶质之间静电相互作用方面的局限性。其中包括这样一个事实，即溶质电荷源通常被建模为位于原子中心的点电荷，而这种对量子力学电荷密度的粗略近似被认为是建模误差的主要来源。此外，在这个点电荷模型中，没有考虑极化这一解释外加电场下电子密度重新分布的重要物理现象。该项目将发展一种新的与原子可极化多极(PM)力场相关的非线性泊松-玻尔兹曼(PB)模型来描述自洽极化过程，并研究永久多极、诱导偶极和反应场势之间的静电相互作用。与线性化的PB(NPB)方程相比，PM源与非线性PB(NPB)方程的耦合在许多方面具有挑战性，包括建模和数值困难，如电荷奇异性、几何复杂性、界面跳跃、非线性、极化以及高计算成本。为了克服这些困难，将开发一套高效、准确和无缝耦合的数值方法来解决与PM-NPB模型相关的数值挑战。特别是，多极电荷奇异性的正则化使用基于格林函数的分解；自洽极化，包括在分子界面重复求解NPB方程，通过结合快速3D增强匹配界面和边界(AMIB)方法的线性化迭代算法有效地实现。最后，将进行模型基准和生物应用，以确保研究结果为模拟静电相互作用提供强大的工具。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。

This collaborative research project aims to improve the implicit solvent modeling for studying electrostatic interaction between solutes, such as proteins, DNA, and RNA, and their surrounding solvent environment. The research will improve on current approaches and will formulate a new polarizable multipole implicit solvent model with improved and enhanced modeling accuracy. Furthermore, efficient and accurate numerical algorithms will be developed to meet computational challenges of the new model. This research will provide biophysicists a new tool for analyzing electrostatic interactions of solvated biomolecules in the form of models and algorithms implemented in a freely available software package. In addition, this project will offer interdisciplinary research and training opportunities for undergraduate and graduate students in biological modeling, computation, and mathematical analysis.The project will address limitations in the existing implicit solvent models for studying electrostatic interaction between solutes. These include the facts that the solute charge sources are often modeled as point charges located at atomic centers, and this rough approximation to the quantum mechanical charge density is known to be a major source of the modeling errors. Moreover, polarization, an important physical phenomenon account for the redistribution of the electron density in the presence of an external electric field is missing in this point charge model. The project will develop a novel nonlinear Poisson-Boltzmann (PB) model associated with an atomic polarizable multipole (PM) force field to describe the self-consistent polarization process and study electrostatic interactions among permanent multipoles, induced dipoles, and reaction-field potential. The coupling of PM source with the nonlinear PB (NPB) equation, as opposed to the linearized PB, is challenging in many aspects involving modeling and numerical difficulties such as charge singularities, geometric complexity, interface jumps, nonlinearity, polarization, as well as high computational cost. To overcome such difficulties, a set of efficient, accurate, and seamlessly coupled numerical methods will be developed to resolve numerical challenges associated with the PM-NPB model. In particular, multipole charge singularities are regularized using Green’s function based decomposition; self-consistent polarization, which involves repeatedly solving an NPB equation across the molecular interface, is efficiently realized by a linearized iterative algorithm coupled with a fast 3D Augmented Matched Interface and Boundary (AMIB) method. Finally, model benchmarking and biological applications will be carried out to ensure that the research results provide a robust tool for simulating electrostatic interactions.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.