Modeling Aqueous Solvation in Biology

生物学中的水溶剂化建模

• 批准号: 8884732
• 负责人: Ken A Dill
• 金额: $ 31.84万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884732
• 关键词: Alzheimer' s Disease; Amber; Amyloid; Antibodies; Basic Science; Binding; Biological; Biological Process; Biology; Cataract; Cells; Collaborations; Communities; Complex; Complex Mixtures; Computer Simulation; Crystallization; Development; Dill; Dimerization; Disease; Drug Formulations; Entropy; Environment; Excipients; Eye Lens Protein; Free Energy; Hand; Ions; Ligand Binding; Liquid substance; Mechanics; Methods; Microscopic; Modeling; Monoclonal Antibodies; Muramidase; Parkinson Disease; Pharmaceutical Preparations; Physics; Precipitation; Process; Property; Proteins; Research Personnel; Salts; Sampling; Series; Sodium Chloride; Solubility; Solutions; Solvents; Source; Statistical Mechanics; Surface; Temperature; Time; Update; Viscosity; Water; amyloid formation; aqueous; atomic interactions; base; design; dipole moment; driving force; improved; intermolecular interaction; molecular dynamics; molecular recognition; nanomachine; prevent; protein aggregation; protein complex; protein folding; protein protein interaction; public health relevance; research study; structural biology; theories; tool; web site

 DESCRIPTION (provided by applicant): In this project, long-time collaborators Dill, Fennell and Vlachy propose experiments and theory to improve computational models of solvation in complex protein solutions. Explicit- and implicit-solvent models have grown increasingly powerful, but are not able to handle important challenges in modeling proteins in concentrated environments, or in high-salt environments, or in the complex formulations of biological drugs (monoclonal antibodies). Researchers cannot yet reliably compute protein aggregation, solubilities, solution viscosities, the formation of amyloid oligomers or fibrils, or Hofmeister effects, nor can they yet rationally design solution formulations that prevent the precipitation of biologicals, or design optimal conditions for protein crystallization. The specific aims here are: (1) Statistical mechanics solution theory and systematic experiments on protein type, concentration and salt-series. To apply a new statistical mechanical approach (Wertheim theory for strongly-associating media applied to the KVD model of protein solutions) to treat complex multicomponent mixtures of proteins, with salts and excipients over a range of concentrations, and as a function of temperature. This is a bottom-up first-principles approach (based on a Hamiltonian of all the intermolecular interactions), not based on averaged-solvent such as implicit-solvent or DLVO approaches. There is a huge need for systematic studies of protein association, pairwise and multimeric, vs. salts and conditions. This will be done by Vlachy's group, which has long-standing expertise, and in conjunction with collaborators at Amgen. Extensive preliminary theory and experiment results are in hand. (2) SEA Water and i-PMF. Fast physical simplified models of solvation at the atomistic scale for solvation free energies and PMFs are in development. Recent proofs show SEA Water is as accurate as explicit-solvent and as fast as implicit-solvent. (3) Making our methods available. SEA water methods will be shared with the scientific community by incorporating them into standard molecular dynamic simulation packages like OpenMM and Amber. Additional solubility prediction tools will be offered on a website.

 描述（由申请人提供）：在该项目中，长期合作者Dill，Fennell和Vlachy提出了实验和理论，以改进复杂蛋白质溶液中溶剂化的计算模型。显式和隐式溶剂模型已经变得越来越强大，但无法处理在浓缩环境中，或在高盐环境中，或在生物药物（单克隆抗体）的复杂配方中建模蛋白质的重要挑战。研究人员还不能可靠地计算蛋白质聚集、溶解度、溶液粘度、淀粉样蛋白低聚物或原纤维的形成或霍夫迈斯特效应，他们也不能合理地设计防止蛋白质沉淀的溶液配方。 生物制品，或设计蛋白质结晶的最佳条件。具体目标是：（1）蛋白质类型、浓度和盐系的统计力学求解理论和系统实验。应用一种新的统计力学方法（适用于蛋白质溶液KVD模型的强缔合介质的Wertheim理论）来处理复杂的多组分蛋白质混合物，盐和赋形剂在一定浓度范围内，并作为温度的函数。这是一种自下而上的第一性原理方法（基于所有分子间相互作用的哈密顿量），而不是基于平均溶剂，如隐式溶剂或DLVO方法。有一个巨大的需要系统的研究蛋白质协会，成对和多聚体，与盐和条件。这将由Vlachy的团队完成，该团队拥有长期的专业知识，并与安进的合作者合作。广泛的初步理论和实验结果在手。(2)海水和i-PMF。溶剂化自由能的原子尺度溶剂化快速物理简化模型 PMF正在开发中。最近的实验证明，海水与显溶剂一样准确，与隐溶剂一样快速。(3)使我们的方法可用。海水方法将与科学界分享，将其纳入标准分子动态模拟软件包，如OpenMM和Amber。其他溶解度预测工具将在网站上提供。