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. Keywords: Membrane protein structure and function; protein-lipid interactions; ion channels; cholesterol drug specificity; molecular dynamics; free energy; potential of mean force; coarse graining There is growing evidence that the function of many membrane proteins involves conformational changes in transmembrane domains. These conformational changes will be modulated by the properties of the host bilayer, in specific and non-specific ways. While experiment provides ample evidence of this regulation, the underpinning mechanisms remain unclear. Whereas the specific interactions will depend on the 3D protein (and drug) structure, the effects of bilayer modifications are likely to be general, and it becomes important to understand these perturbations to guide the development of specific drugs. A series of simulations are described to develop realistic models of membrane-protein systems, observe and quantify the short and long ranged bilayer perturbations due to the presence of membrane proteins, and to investigate methods for quantitative descriptions of protein-lipid interactions. This will set the groundwork for elucidating the mechanisms of protein function modulation. This medium PACI allocation will demonstrate the viability of such methods for studying this important problem, and set the stage for future allocations that will directly tackle the issue of the modulation of cell membrane-bound protein function. Ultimately, explaining the influence of changes in the bilayer environment is a necessary step to bridge the gap between structure and function.
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