Modeling Aqueous Solvation in Biology

 描述(由申请人提供)：在这个项目中，长期的合作者Dill，Fennell和Vlachy提出了改进复杂蛋白质溶液中溶剂化计算模型的实验和理论。显式和隐式溶剂模型已经变得越来越强大，但不能处理在浓缩环境、高盐环境或复杂的生物药物配方(单抗)中对蛋白质进行建模的重要挑战。研究人员还不能可靠地计算蛋白质的聚集度、溶解度、溶液粘度、淀粉样寡聚体或纤维的形成或霍夫迈斯特效应，也不能合理地设计防止蛋白质沉淀的溶液配方。 生物制剂，或设计蛋白质结晶的最佳条件。具体内容为：(1)统计力学溶液理论及蛋白质种类、浓度和盐系的系统实验。应用新的统计力学方法(强缔合介质的Wertheim理论应用于蛋白质溶液的KVD模型)来处理复杂的多组分蛋白质混合物，包括浓度范围内的盐和辅料，以及作为温度的函数。这是一种自下而上的第一原理方法(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。对蛋白质相互作用、成对和多聚体、与盐和条件的系统研究是非常有必要的。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已在手中。(2)海水和I-PMF。溶剂化自由能和原子尺度上溶剂化的快速物理简化模型 PMF正在开发中。最近的证据表明，海水与显性溶剂一样准确，与隐式溶剂一样快速。(3)使我们的方法可用。海水方法将与科学界共享，将它们纳入标准的分子动力学模拟包，如OpenMM和Amber。网站上将提供额外的溶解度预测工具。

 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.