Membrane transporters are principal players in active exchange of materials across the cellular membrane, one of the most fundamental and highly regulated processes in living cells. Investigating the molecular basis of their function, therefore, is of utmost importance in various disciplines of biological and biomedical research. These complex proteins provide highly sophisticated, operationally fine-tuned molecular machines to efficiently couple various sources of energy in the cell to vectorial translocation of various molecular species across the membrane against their chemical gradient. Investigation of the molecular details of the mechanism of membrane transporters poses a major challenge, primarily due to their structural complexity and the high dimensionality of the process of energy-dependent transport furnished by them. Substrate binding and translocation along the permeation pathway in membrane transporters is closely coupled to numerous stepwise protein conformational changes of various magnitudes that are induced and/or coordinated by the energy- providing mechanisms, e.g., binding and co-transport of protons and other ions, or binding and hydrolysis of ATP. A detailed description of the mechanism of transport in membrane transporters, therefore, relies on methods that can describe the dynamics of these processes at an atomic level. Molecular dynamics simulation remains a highly relevant approach with sufficient temporal and spatial resolutions to investigate such processes. Application of the method to membrane transporters is a very young area of research, since sufficient structural data required for such simulations has become available only recently. Furthermore, in order to describe biologically relevant events and steps involved in the function of membrane transporters, atomistic simulations of these large biomolecules on the orders of at least 0.1-1
Public Health Relevance
Membrane transporters are proteins that mediate selective transport of a wide range of materials, e.g., nutrients, hormones, and neurotransmitters, across the cellular membrane. They are essential to almost all aspects of human physiology, and their malfunction is associated with a large number of human diseases. The research proposed in this application will investigate the mechanism of function of several membrane transporters at a molecular level.
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