CAREER: Self-Assembly Through Water-Mediated Interactions: A New Statistical Thermodynamics and Simulations Approach

摘要CTS-0134255 Garde，ShekharRensselaer Polytechnic InstituteThe CAREER提案的目标是开发一个成功的研究计划，利用对水介导的相互作用的基本理解，对溶液中生物分子自组装过程进行定量分子建模。 它提出了一个愿景，结合统计力学理论与新的有效的分子模拟技术，开发一个通用的方法来研究生物分子相互作用的热力学，结构和动力学方面。 一般来说，溶液中生物分子的定量建模，特别是蛋白质，是化学工程师感兴趣的，因为它与生物技术和制药应用，设计新型自组装材料以及分子医学中的应用直接相关。 该项目特别关注T，P，盐和共溶剂对蛋白质稳定性和溶液中相互作用的影响。 为此，提出了研究的具体步骤：1. (a)使用原子级详细模拟和理论，量化由水介导的各种“原型”（构建模块或蛋白质组分）溶质之间的相互作用。 (b)开发，第一次，一个广泛的图书馆的距离依赖于自由能的溶质-溶质在水中的相互作用-平均力（PMFs）的潜力-原型溶质作为温度，压力，盐和共溶剂浓度的函数。2.开发一种通用的、高效的统计力学方法，该方法将PMF库中包含的水介导的相互作用应用于水中的各种自组装过程。 将这种预测方法应用于蛋白质热力学作为各种环境应力的函数的研究。 对选定的测试系统进行补充性的大规模显式水模拟，以研究进一步的机理细节，评估预测和微调。

Abstract CTS-0134255Garde, ShekharRensselaer Polytechnic InstituteThe goal of the CAREER proposal is to develop a successful research program for quantitative molecular modeling of biomolecular self-assembly processes in solution using fundamental understanding of the underlying water-mediated interactions. It presents a vision for combing statistical mechanical theories with novel efficient molecular simulation techniques to develop a generalized approach to study thermodynamic, structural, and kinetic aspects of biomolecular interactions. Quantitative modeling of biomolecules in solution, in general, and proteins in particular is of interest to chemical engineers because of its direct relevance to biotech and pharmaceutical applications, designing novel self-assembling materials, and applications in molecular medicine. This project focuses specifically on the T, P, and salt and cosolvent effects on protein stability and interactions in solution. To this end, the specific steps in the proposed research are:1. (a) To quantify, using atomically detailed simulations and theory, interactions between various "archetype" (building blocks or protein constituents) solutes mediated by water. (b) To develop, for the first time, an extensive library of the distance dependent free energies of solute-solute interactions in water- the potentials of mean force (PMFs) - for archetype solutes as a function of temperature, pressure, and salt and cosolvent concentration. 2. To develop a general and highly efficient statistical mechanical approach that integrates water-mediated interactions contained in the PMF-library for applications to a variety of self-assembly processes in water.3. To apply this predictive approach to study of protein thermodynamics as a function of various environmental stresses. Perform complementary large-scale explicit water simulations for selected test systems for investigation of further mechanistic details, assessment of predictions, and fine-tuning.