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

ShekharRensselaer理工学院CTS-0134255 Garde职业计划的目标是开发一个成功的研究计划，利用对潜在的水介导的相互作用的基本理解，对溶液中的生物分子自组装过程进行定量分子模拟。它提出了将统计力学理论与新的有效的分子模拟技术相结合的愿景，以开发一种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。对溶液中的生物分子，特别是蛋白质的定量建模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在分子医学中的应用直接相关。这个项目特别关注T、P、盐和助溶剂对蛋白质稳定性和溶液中相互作用的影响。为此，拟议研究中的具体步骤是：1.(A)利用原子详细的模拟和理论，量化水介导的各种“原型”(构件或蛋白质成分)溶质之间的相互作用。(B)首次建立一个广泛的溶质-溶质相互作用自由能随距离变化的资料库--平均力势(PMF)--作为温度、压力、盐和助溶剂浓度的函数的原型溶质。2.开发一种通用和高效的统计机械方法，该方法集成了PMF库中包含的水介导的相互作用，用于应用于水中的各种自组装过程。将这一预测性方法应用于研究蛋白质热力学随各种环境压力的变化。对选定的测试系统执行补充的大规模显式水模拟，以调查进一步的机械细节、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.