LARGE SCALE SIMULATIONS OF MEMBRANE CHANNELS AND TRANSPORTERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Selective transport of materials across the membrane is a major undertaking for a living cell. Due to the hydrophobic barrier of the cellular membrane against diffusion of water-soluble materials, for almost every compound a specialized protein has been evolved that facilitates the crossing of the desired substrate in a very selective manner. It is estimated that more than half of the genetic material and the energy of a living cell are used for production and function of proteins involved in membrane transport. Therefore, understanding the molecular mechanisms of traffic across biological membranes is of utmost importance in the biology of a living cell, in physiology of higher organisms, and in medicine. The problem of selective permeation and transport is clearly a molecular problem, and the underlying mechanisms can only be understood at an atomic resolution. Computer simulation of atomistic models of membranes and membrane proteins has been very successful in describing structural and dynamical aspects of such systems in relation to their function. Furthermore, atomic resolution structures of several membrane channels and transporters have been solved. These structures along with the available simulation methodologies have set the stage for us to investigate at a molecular level the structural basis of selectivity and function in this important family of membrane proteins. Several membrane channels and transporters are proposed to be investigated in this proposal. Three of the projects will continue to study the mechanisms of permeation, selectivity, and gating in aquaporins. Channel-mediated gas transport and gas diffusion across pure lipid bilayers are the subject of the next project, in which transport of physiologically relevant gas species, O2, CO2, CO, and NO, across the cellular membrane will be investigated. The next project will address gating and selective ion permeation in a voltage gated K channel. The last two projects will investigate two active transporters. In the first one, the mechanism of coupling of proton and sugar transport in lactose permease, the most experimentally investigated member of the Major Facilitator Superfamily, will be studied. The second project will address the mechanism of force propagation between the inner and outer membranes in transport of vitamin B12 by BtuB. The proposed simulation studies all address fundamental membrane transport processes, and are among the most exciting problems in biomedical research. All projects, conducted in close collaborations with leading experimental groups, require long simulations of large systems, and, thus, can only be accomplished with the advanced computational resources provided at national supercomputing centers. As such they represent new opportunities for high performance computing to drive progress in some of the most exciting areas of biomedicine.