RUI: Multiscale Models for ABC Transporter Molecular Dynamics

University Of New England, Biddeford ME

Investigators

Abstract

Understanding the dynamics of biomolecules at the cell surface, including how molecules move across the cell membrane, is crucial to the basic understanding of life processes. The cell membrane normally acts as a barrier that selectively limits what enters the cell. This project explores the mechanisms by which transporters, or large proteins that reside in the cell membrane, actively export substances across the cell membrane. Multiscale simulations are developed to predict molecular behavior of these transporters. The project provides undergraduate and high school students from underrepresented groups in rural Maine with training in the scientific method, computational analysis, and molecular science--approaches vital to further advances in knowledge and society. A weeklong summer workshop has been established to introduce Maine students to Unix programming and protein modeling. Student researchers are involved in carrying out all aspects of the research and receive advanced training in the theoretical foundations of statistical thermodynamics. Returning students acquire teaching experience by co-facilitating summer workshops, interactive biochemistry classes, and molecular visualization labs. Experimental collaborators trapped the E. coli ABC transporter, MsbA, in distinct states of its conformational cycle, including open and closed inward-facing conformers and an outward-facing post-hydrolysis conformation. Paramagnetic spin label measurements subsequently confirmed the ATP-dependent alternating accessibility of the transmembrane protein chamber to the intra- and extracellular bilayer leaflets. This project connects these existing structural data with a functional picture of the dynamic molecular interactions that accompany protein conformational cycling and couple ATP hydrolysis to substrate translocation. Consistent with the Integrating Across Scales priority of the Division of Molecular and Cellular Biosciences, a multiscale description is developed from atomistic simulations to simulate the dynamics of a large molecular machine residing in its lipid bilayer environment. The role of annular phospholipid solvation on translocation of the flippase's lipid substrate is specifically explored. The force field lipid and protein parameter set created by the project is not limited to transporters and is of general utility for simulations of membrane protein systems, their diffusive dynamics, and molecular interactions. Undergraduate and high school students from underrepresented groups are incorporated and trained in the foundations of computational science.