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.
