Multi-scaled Modeling of Electrostatic and Polarization Effects in Biomolecules

项目摘要 生物分子的基于物理的原子模拟提供了一系列可测试的可观测量， 很大程度上无法通过实验获得的机械论见解。然而，具有挑战性的过程，如 有序-无序转变、离子相互作用和生物膜附近的界面事件很难建模 在数量上与现有的方法。困难来自于精确建模的要求， 不同结构状态和不同溶剂相的静电和极化效应。这并不容易 如果我们要求我们的原子模型对典型的分子过程足够有效，就可以实现。我们 解决准确性问题的中心假设是不同溶剂相中的生物分子和 不同的结构状态只能在可极化静电学中以令人满意的可传递性来建模 框架。在现有方法的一个重大转变中，我们正在探索一种可极化的高斯多极 模型，其中所有电荷和多极子由高斯密度而不是经典点表示。对 另一方面，偏振处理总是降低模拟效率，导致更明显的 效率问题。因此，与现有方法的第二个主要区别是我们同时关注效率 基于多尺度框架，具有全原子极化、粗粒度极化和连续性 极化模型，它们彼此一致。这使得它们能够更容易地与 多尺度模拟方法我们的计划可以概括为以下四个方面。首先，我们将开发 一种新型的可极化力场其次，我们将发展和扩展连续极化溶剂模型 与新的极化力场一致第三，一个粗粒度的极化力场将被开发。 最后，我们将继续应用我们的计算模型和工具来研究有趣的生物医学问题 最能体现新车型潜力的车型。我们将同时推广新的模式， 积极影响生物医学界的工具。通过这些有关努力，我们将提供 一组多尺度的计算机模型来模拟生物分子的静电和极化， 一系列具有生物医学重要性的有趣系统。

Project Summary Physics-based atomistic simulations of biomolecules offer a range of testable observables, providing critical mechanistic insights that are largely inaccessible to experiment. However challenging processes, such as order-disorder transitions, ionic interactions, and interface events near biomembrane, are difficult to model quantitatively with existing approaches. The difficulty comes from the requirement of accurate modeling of electrostatic and polarization effects in different structural states and different solvent phases. This is not easily achievable if we demand that our atomistic model is efficient enough for typical molecular processes. Our central hypothesis to address the accuracy issue is that biomolecules in different solvent phases and in different structural states can only be modeled with satisfactory transferability within polarizable electrostatics frameworks. In a major shift from existing approaches, we are exploring a polarizable Gaussian Multipole model, where all charges and multipoles are represented by Gaussian densities instead of classical points. On the other hand polarization treatments invariably reduce simulation efficiency, leading to a more pronounced efficiency issue. Thus a second major difference from existing approaches is our concurrent focus on efficiency based on a multi-scaled framework with all-atom polarizable, coarse-grained polarizable, and continuum polarizable models, which are consistent with each other. This allows them to be more easily interfaced in multi-scaled simulation methods. Our plan can be summarized in the following four areas. First we will develop a novel polarizable force field. Second we will develop and extend continuum polarizable solvent models consistent with the new polarizable force field. Third a coarse-grained polarizable force field will be developed. Finally, we will continue to apply our computational models and tools to study interesting biomedical problems that best demonstrate the potentials of the new models. We will concurrently disseminate the new models and tools to positively impact the biomedical community. Through these concerned efforts, we will offer the community a multi-scaled set of computer models to model biomolecular electrostatics and polarization for a range of interesting systems of biomedical importance.