Collaborative Research: Boundary Integral Simulations for Solvent Effects in Protein Structure and Dynamics

蛋白质是大的生物分子，每个分子都由一个具有复杂三维结构的独特的氨基酸序列组成。蛋白质在生物体中发挥着许多重要的功能，有些疾病与蛋白质结构不正确有关。因此，生物医学研究人员对了解蛋白质的结构、动力学和功能非常感兴趣。在它们的自然环境中，蛋白质被含有溶解盐的水所包围；蛋白质/溶剂的相互作用对生物体的正常功能至关重要。实验室实验被用来研究这些蛋白质/溶剂的相互作用，但计算机模拟也越来越多地被用来补充实验。研究人员将利用他们在计算数学方面的专业知识，开发用于计算蛋白质/溶剂相互作用的改进的数值算法和软件，这可能会对蛋白质折叠和合成药物设计等领域产生影响。将与生物科学家合作研究几种应用。开发的软件将以开源格式发布在公共网站上，并将安装在广泛分发的分子模拟软件包中，供生物计算研究人员使用。该项目将在这一重要的科学研究分支培养一名博士后和一名研究生。该项目将开发用于计算静电溶剂效应的改进的数值算法和软件，静电溶剂效应在确定蛋白质结构、动力学和功能方面发挥关键作用。计算这些影响是具有挑战性的，而基于泊松-玻尔兹曼(PB)静电势(PB)方程的隐式溶剂模型是降低成本的一种流行方法。然而，由于代表蛋白质的奇点电荷、分子表面复杂的几何结构和不连续的介电常数以及无限的计算区域，基于网格的PB模拟遇到了困难。在之前由NSF支持的研究中，研究人员开发了一种新的树编码加速边界积分(TABI)势能求解器，具有更高的精度和效率、低内存使用量和直接的并行化。当前项目包含以下组件。1.(算法开发)研究人员将扩展当前的Tabi势求解器，以计算分子动力学模拟所需的静电溶剂化力。这需要对代表分子表面感应电荷的奇异积分进行仔细的离散化，将低介电性蛋白质结构域与高介电性溶剂域分开。2.(并行计算)研究人员将为图形处理单元(GPU)开发一种新的并行Tabi解算器，利用树码对内存和通信的低要求。3.(生物应用)研究人员将应用新的Tabi势能求解器和驱动力来研究蛋白质中的溶剂效应。将与生物科学家合作研究的应用包括：(A)杀菌凝集素蛋白的pH依赖性质；(B)与自身免疫性疾病相关的离子环境中神经递质受体的结构变化；(C)Tabi的扩展，包括可极化的原子多极溶质。

Proteins are large biomolecules each consisting of a unique sequence of amino acids with a complex three-dimensional structure. Proteins perform many essential functions in living organisms, and some diseases are associated with improper protein structure. Hence there is great interest among biomedical researchers in understanding the structure, dynamics, and function of proteins. In their natural environment proteins are surrounded by water with dissolved salt; the protein/solvent interactions are critical to proper function in the organism. Laboratory experiments are used to study these protein/solvent interactions, but computer simulations are also increasingly employed to complement the experiments. The investigators will use their expertise in computational mathematics to develop improved numerical algorithms and software for computing protein/solvent interactions, with potential impact on areas such as protein folding and synthetic drug design. Several applications will be studied in collaboration with bioscientists. The software developed will be posted in open source format on a public website and will be installed in a widely distributed molecular simulation software package for use by bio-computational researchers. The project will train a postdoc and a graduate student in this important branch of scientific research. The project will develop improved numerical algorithms and software for computing electrostatic solvent effects which play a key role in determining protein structure, dynamics, and function. Computing these effects is challenging, and implicit solvent models based on the Poisson-Boltzmann (PB) equation for the electrostatic potential are a popular approach to reducing the cost. However, grid-based PB simulations encounter difficulties due to the singular point charges representing the protein, the complex geometry and discontinuous dielectric constant across the molecular surface, and the unbounded computational domain. In previous NSF-supported research, the investigators developed a new treecode-accelerated boundary integral (TABI) potential solver with improved accuracy and efficiency, low memory usage, and straightforward parallelization. The current project has the following components. 1. (algorithm development) The investigators will extend the current TABI potential solver to compute the electrostatic solvation forces needed for molecular dynamics simulations. This requires careful discretization of singular integrals representing the induced charge on the molecular surface separating the low-dielectric protein domain from the high-dielectric solvent domain. 2. (parallel computing) The investigators will develop a new parallel TABI solver for graphics processing units (GPUs), taking advantage of the treecode's low memory and communication requirements. 3. (biological applications) The investigators will apply the new TABI potential solver and force driver to study solvent effects in proteins. Applications to be studied in collaboration with bioscientists include: (a) pH-dependent properties of a bactericidal lectin protein; (b) structural changes of a neurotransmitter receptor in an ionic environment which is relevant to an autoimmune disease; (c) extension of TABI to incorporate polarizable atomic multipole solutes.