Cellular Crowding Effects of Biomolecular Stability and Dynamics

智力优势：细胞环境由密集的、不均匀的生物分子溶液组成，与结构生物学中通常考虑的稀释的、均匀的条件有很大不同。考虑由此产生的拥挤效应对于充分理解细胞环境中的生物分子功能至关重要。模拟与现实模型的细胞蛋白质和核酸被用来检查拥挤的物理化学效应。主要目标是更好地理解分子间相互作用和溶剂性质改变对拥挤时生物分子稳定性的作用。所进行的模拟涉及的模型范围从完全原子的显式溶剂表示到多尺度模型，其中溶剂和/或溶剂以简化的方式建模。模拟的结果对于开发有效的细胞环境模型至关重要，这些模型在当时是不可用的，但迫切需要大规模的细胞动力学模拟。更广泛的影响：对社会更广泛的影响将是从物理角度更全面地了解细胞过程。更具体地说，该研究旨在将详细的分子水平的生物学理解与细胞和系统水平上发生的过程联系起来。最终，这种见解将允许基于物理原理的详细硅细胞模型的发展，可以查询以了解复杂的生物过程。这里提出的研究将催化一些更具体、更广泛的影响：在物理、生物和计算科学的界面上对学生进行跨学科培训，包括来自物理和生物科学的研究生和本科生团队；促进妇女的参与；通过密歇根州立大学的IDEAS项目，重点从代表性不足的少数族裔中招收本科生；增强广泛使用的建模软件；促进与日本理化研究所的国际合作，包括为参与该项目的学生提供短期海外研究访问；通过传统渠道广泛传播研究成果，并通过向非专业观众公开演讲进行公共宣传。

Intellectual Merit:Cellular environments consist of dense, heterogeneous solutions of biomolecules that differ significantly from the dilute, homogeneous conditions typically considered in structural biology. A consideration of the resulting crowding effects is essential to fully understand biomolecular function in cellular environments. Simulations with realistic models of cellular proteins and nucleic acids are used to examine the physicochemical effects of crowding. The main goal is to better understand the role of intermolecular interactions and altered solvent properties on biomolecular stability upon crowding. The simulations carried out involve models ranging from fully atomistic explicit solvent representations to multi-scale models where solvent and/or crowders are modeled in a simplified fashion. The results from the simulations are essential for developing effective models of cellular environments that are unavailable at the time but urgently needed for large-scale simulations of cellular dynamics.Broader Impacts:The broader impact to society will be a more comprehensive understanding of cellular processes from a physical perspective. More specifically, the research aims to connect the detailed molecular-level understanding of biology to processes occurring on cellular and systems levels. Ultimately, such insight will allow the development of detailed in silico cellular models based on physical principles that can be queried to understand complex biological processes. A number of more specific broader impacts will be catalyzed by the research proposed here: Interdisciplinary training of students at the interface of physical, biological, and computational sciences, both graduate students and teams of undergraduate students from physical and biological sciences; promotion of the involvement of women; focused efforts to recruit undergraduates from underrepresented minorities through the IDEAS program at MSU; enhancement of widely used modeling software; promotion of an international collaboration with RIKEN in Japan including short-term research visits abroad for students involved in the project; and broad dissemination of research results through traditional channels as well as public outreach through public presentations to lay audiences.