In this research project, the PI will study the effects of the cellular environment on the structure and folding dynamics of proteins and will train students in this area of research. Proteins perform a variety of biological specific functions inside cells, operating in a crowded matrix with many other macromolecules. The PI will recruit minority and female undergraduate students for her research program from introductory physics courses that she teaches to retain their interest in science. The University of Houston (UH) is a designated Hispanic-serving institute with over 40,000 students. The PI is a director of the Physics Science Teaching Equity Project (Physics STEP), a professional develop program for continuing education. The focus of Physics STEP is to provide training to 20 in-service non-physics teachers who are assigned to teach high-school physics each year. These 20 teachers teach a total of 3000 high-school students from high-need school districts at the greater Houston area. The opportunity for young students and teachers to learn physics would greatly improve the science literacy of our future generation. In collaboration with the College of Education at UH, the Physics STEP offers each teacher content knowledge and pedagogy, including "inquiry-based" experiments on selected physics topics through a yearly curriculum. The PI plans to recruit high-school students to join her research program by pairing them with teachers who participate in the Physics STEP. Additionally, through coordination with science teachers of elementary schools in STEP, the PI will reach out to fourth- and fifth-grade students by participating in a Career Day and by hosting science field trips at the UH campus. The PI will use her extensive teacher's network and experience to enhance the broader impacts of the research. In the long term, this methodology may help reveal molecular mechanisms of cellular adaptation and regulation of protein networks in response to stress cues. The dissemination of the developed computer program through the internet will promote modeling tools that are freely available to study protein-folding in cells.
The objective of the research is to characterize the effects of the cellular environment on the structure and folding dynamics of model proteins. Most experiments, theories, and simulations on the structures and folding dynamics of proteins have been addressed in dilute solutions in test tubes, which are not representative of the congested biological environment in cells. The extent to which the competing effects of the cellular environment affect protein biophysics is poorly understood. There is an urgent need for the development of theories and computational methods to provide a quantitative understanding of the environmental effects that dictate protein structures and conformational dynamics in cells. Only with tools to quantitatively assess protein biophysics inside cells can a fundamental understanding of protein's behaviors in response to cellular signaling cues be achieved. The research includes three integrated directions: First, the principal investigator (PI) will apply computer simulations to quantify folding kinetics in the presence of chemical denaturants and crowded media and relate these results to similar in vitro experiments. This will allow the investigation of transition-state structures and possible movements of the transition states of protein folding in cell-like media, which can then inform the design of further in vitro experiments. Next, the PI will develop a quantitative description between energy landscape profiles and protein-folding kinetics in crowded environments, which is essential to better understand the underlying physical principles behind computer simulations and in vitro experimental data. Finally, the PI will combine computer simulations, development of improved theories, and collaboration with experimentalists to advance the knowledge of how competing cellular effects, such as macromolecular crowding, electrostatics, and hydrodynamic interactions, tune the structures and folding kinetics of proteins in cells. The research is significant because the outcome will offer molecular explanations and predictions that connect residual details of proteins to their folding processes in cells. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Computational Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate.
