This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
Proteins that reside in the cell membrane play important structural roles, but they are also critical to the cell's ability to sense and respond to environmental stimuli. For instance, ion channels open in response to changes in membrane voltage or membrane tension to permit the flow of molecules into and out of the cell. Knowledge of how proteins interact with the membrane is essential to our understanding of these functions. The research goal of this project is to build and use computational tools for elucidating the nature of membrane proteins' interactions with the membrane. Such tools are needed to understand the folding and trafficking of proteins from the endoplasmic reticulum (ER) to the plasma membrane and to understand the functional properties of proteins that undergo conformational rearrangements in the membrane. Currently, molecular simulations of charged helical peptides predict membrane insertion energies that are much larger than those derived from experiment. Therefore, new computational approaches are needed to pinpoint the source of these differences and help to resolve them. This CAREER project will (a) allow for the development of a fast, continuum based method for calculating the insertion energies and relative stabilities of membrane proteins, (b) use this computational model to predict the energy and kinetics of protein extraction from the membrane and compare these rates with in vivo extraction experiments from the ER, and (c) study how voltage changes manipulate voltage-sensor proteins to control their behavior. The membrane insertion model will be packaged into a freely available, cross-platform JAVA program with an intuitive graphical interface for carrying out membrane protein energetic calculations.
Broader Impacts. The educational component of this CAREER project involves continued development of a new mathematical biology course that introduces upper division undergraduate students to mathematical concepts that have greatly impacted biology. This project will enable the writing of an undergraduate textbook by the investigator and his colleagues. The undergraduate course and textbook will train future biologists in the mathematics needed to understand cutting-edge technologies in the biological sciences. Additionally, this research program includes the development of a summer course in basic mathematics for high school students who are members of minorities under-represented in science and who are enrolled in the School-to-Career Teen Program (Pittsburgh, PA). It will permit continued math and science education for these high school students and encourage them to attend and succeed at post-secondary educational institutions.
