This project focuses on understanding the molecular factors that govern gene expression. To this end, large-scale simulations will be applied to study how the ribosome can accurately and efficiently synthesize proteins. The production of proteins is essential for nearly all biological functions, making the ribosome one of the most important biological machines. While modern experiments can resolve static configurations of the ribosome, detailed simulations will allow the research community to understand how molecular structure enables specific biological function. This can reveal strategies for controlling cellular dynamics, as well as provide a "rule book" that can aid in the design of novel molecular-scale machines. This project will involve a range of activities that will provide introductory science seminars for high school students, valuable training experiences for undergraduate and graduate student researcher and workshops for experimental researchers.
Theoretical models will be developed and applied to identify the detailed role of localized, "diffuse" ions during ribosome function. Characterizing several critical substeps of the elongation cycle (tRNA accommodation, hybrid-state formation, translocation and domain rotations) will elucidate how the ionic environment shapes the energy landscape of the ribosome. This will help uncover the modes by which ions can enable conformationally-complex biological dynamics. With the high negative charge density of RNA, the dynamics of ribonucleoprotein assemblies rely critically on a locally diffuse ionic environment, which can lead to attraction between negatively charged RNA molecules. Accordingly, to fully characterize the energetics of large-scale biological assemblies, one must properly describe the statistical properties of the ionic environment. To address this challenge, simplified energetic models will be developed that employ all-atom resolution, as well as explicitly represented monovalent and divalent ions. Calibration of the energetic parameters will be established through comparison with experiments and explicit-solvent simulations of prototypical systems. These simplified models will then enable the simulation of large-scale (20-100 Angstroms) conformational transitions in the ribosome. This will implicate the influence of fluctuations/changes in local ionic distributions. While this study will focus on ribosome dynamics, the models and computational methods will be transferrable to a broad range of biological assemblies.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.