Collaborative research: Geometric flow approach to implicit solvation modeling

描述（由申请人提供）：溶剂化是水环境中溶质分子与溶剂或离子之间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涉及生物分子组装体的折叠、相遇、识别和结合的重要生物过程的重要先决条件。溶剂化模型可以大致分为两类：将溶剂视为分子或原子细节的显式溶剂模型和将溶剂视为介电连续体的隐式溶剂模型。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、折叠能的估计、结合亲和力、pKa 值以及结构、突变和许多其他热力学和动力学量的分析。然而，目前大多数隐式溶剂模型都使用关于溶剂-溶质界面的临时假设，这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。在能量最小化时，我们的框架在连续溶剂和离散原子溶质之间生成界面。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。由此产生的方程将用先进的算法求解。广泛的验证和应用旨在确保所提出的多尺度范式产生准确的溶剂化特性。文献中数以千计的应用证明了隐式溶剂模型的重要性。该研究通过引入新的数学框架来构建物理界面，解决了现有模型中因溶剂-溶质界面的临时假设而产生的严重局限性。总的来说，该提案为生物分子建模的重要领域提供了一种创新方法。

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.