Collaborative research: Geometric flow approach to implicit solvation modeling

合作研究：隐式溶剂化建模的几何流方法

• 批准号: 8309088
• 负责人: Guowei Wei
• 金额: $ 30.79万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309088
• 关键词: Address; Affinity; Algorithms; Area; Automobile Driving; Behavior; Binding; Biological; Biological Models; Biological Process; Biology; Biomedical Research; Charge; Chemical Models; Chemicals; Chemistry; Commit; Communities; Computer software; Computer-Aided Design; Coupled; Drug Design; Education; Educational Curriculum; Educational process of instructing; Educational workshop; Electrostatics; Ensure; Environment; Equation; Equilibrium; Evaluation; Fostering; Free Energy; Freedom; Ions; Kinetics; Lead; Link; Liquid substance; Literature; Mathematical Biology; Mechanics; Methodology; Methods; Microscopic; Modeling; Molecular; Molecular Models; Molecular Structure; Mutation; Physics; Process; Property; Research; Research Personnel; Sampling; Solvents; Structure; Students; Surface; Surface Properties; Surface Tension; System; Thermodynamics; Titrations; Training Support; Validation; Variant; aqueous; base; design; experience; image processing; innovation; interest; intermolecular interaction; molecular modeling; multi-scale modeling; physical property; pressure; programs; simulation; software development; solute

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 selfconsistently 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 .

溶剂化是在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对涉及折叠，相遇，识别和结合的重要生物过程进行定量描述和分析的必要先决条件。 生物分子组件。溶剂化模型可以大致分为两类：显式将溶剂处理分子或原子细节以及隐式溶剂模型，这些模型将溶剂视为介电连续性。 由于其效率，隐式溶剂模型已在各种生物学应用中非常流行，包括合理的药物设计，折叠能量的估计，结合亲密关系，PKA值以及结构，突变以及许多其他热力学和动力学量的分析。但是，临时 目前，大多数隐式溶剂模型都使用了有关溶剂 - 溶剂接口的假设，从而阻碍了它们的可靠性，准确性和效率。 提出的项目通过开发基于差异几何的多尺度框架来解决此问题。能量最小化后，我们的框架会在连续溶剂和离散原子溶质之间产生界面。特别是，完整的自由能函数的变化会导致自耦合耦合的几何和泊松 - 波尔兹曼方程。所得方程将通过高级算法求解。广泛的验证和应用旨在确保所提出的多尺度范式得出准确的溶剂化属性。 文献中成千上万的应用程序支持隐式溶剂模型的重要性。 拟议的研究解决了通过引入一个新的数学框架来构建物理接口的新数学框架，这是由溶剂 - 色界面临时假设产生的严重局限性。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的方法。