Collaborative research: Geometric flow approach to implicit solvation modeling

描述（由申请人提供）：溶剂化是溶质分子与溶剂或离子在水环境中相互作用的基本过程。准确的溶剂化模型是定量描述和分析重要生物过程的必要先决条件，这些过程涉及生物分子组装的折叠、相遇、识别和结合。溶剂化模型大致可分为两类：显式溶剂模型，从分子或原子的细节处理溶剂；隐式溶剂模型，将溶剂视为介电连续体。由于其效率，隐式溶剂模型在各种生物应用中变得非常流行，包括合理的药物设计，折叠能，结合亲和度，pKa值的估计，结构，突变和许多其他热力学和动力学量的分析。然而，目前在大多数隐式溶剂模型中使用了关于溶剂-溶质界面的特殊假设，阻碍了它们的可靠性，准确性和效率。拟议的项目通过开发基于微分几何的多尺度框架来解决这个问题。在能量最小化的情况下，我们的框架产生了连续溶剂和离散原子溶质之间的界面。特别是，全自由能泛函的变化产生自洽耦合几何方程和泊松-玻尔兹曼方程。得到的方程将用先进的算法求解。广泛的验证和应用程序的设计，以确保提出的多尺度范式产生准确的溶剂化性质。隐式溶剂模型的重要性得到了文献中数千个应用的支持。提出的研究通过引入新的数学框架来构建物理界面，解决了现有模型中由于对溶剂-溶质界面的临时假设而产生的严重局限性。总的来说，这一建议为生物分子建模的一个重要领域提供了一种创新的方法。

DESCRIPTION (provided by applicant): Solvation is a fundamental process of interactions between solute molecules and solvent or ions in the aqueous environment. Accurate models of solvation are essential prerequisites for the quantitative description and analysis of important biological processes involving the folding, encounter, recognition, and binding of biomolecular assemblies. Solvation models can be roughly divided into two classes: explicit ones that treat the solvent in molecular or atomic detail and implicit solvent models that treat the solvent as a dielectric continuum. Because of their efficiency, implicit solvent models have become very popular for a variety of biological applications, including rational drug design, estimations of folding energies, binding affinities, pKa values, and the analysis of structure, mutation, and many other thermodynamic and kinetic quantities. However, ad hoc assumptions about solvent-solute interfaces are currently used in most implicit solvent models, impeding their reliability, accuracy and efficiency. The proposed project addresses this problem by developing a differential geometry-based multiscale framework. Upon energy minimization, our framework generates the interface between the continuum solvent and the discrete atomistic solute. In particular, variation of the full free energy functional gives rise to self consistently coupled geometric and Poisson-Boltzmann equations. The resulting equations will be solved with advanced algorithms. Extensive validations and applications are designed to ensure that the proposed multiscale paradigm yields accurate solvation properties. The importance of implicit solvent models is supported by the thousands of applications in the literature. The proposed research addresses serious limitations in existing models arising from ad hoc assumptions of the solvent-solute interface by the introduction of a new mathematical framework to construct physical interfaces. In total, this proposal offers an innovative approach to an important area in biomolecular modeling.