Membrane protein structure in lipido: computational developments. This application is in response to Program Announcement PA-10-228 for Structural Biology of Membrane Proteins. The overall goal of the project is to develop new computational methods for NMR structural analysis of integral membrane proteins within their functional environment of the phospholipid bilayer membrane. These protein/lipid macromolecular complexes can be characterized using NMR spectroscopy. The experimental aspects of biomolecular NMR (sample preparation, instrumentation, pulse sequences) have reached an advanced level;however, computational methods are lagging behind. We propose to close this technology gap with three specific aims designed to facilitate structure determination and increase structural quality. To facilitate structure determination and broaden the impact of our work, our methods will be integrated with widely used programs for NMR structure refinement by restrained molecular dynamics and de novo protein structure prediction. To maximize the structural quality and information content, our methods will be tailored for the membrane-specific structural restraints provided by the experimental data.
Membrane proteins play fundamental roles in human health and are the targets of most human therapeutic drugs. Facilitating their structure determination, as proposed in this project, is critical for advancing medical and pharmaceutical research.
|Tian, Ye; Schwieters, Charles D; Opella, Stanley J et al. (2015) A Practical Implicit Membrane Potential for NMR Structure Calculations of Membrane Proteins. Biophys J 109:574-85|
|Yao, Yong; Fujimoto, Lynn M; Hirshman, Nathan et al. (2015) Conformation of BCL-XL upon Membrane Integration. J Mol Biol 427:2262-70|
|Cheng, Xi; Jo, Sunhwan; Qi, Yifei et al. (2015) Solid-State NMR-Restrained Ensemble Dynamics of a Membrane Protein in Explicit Membranes. Biophys J 108:1954-62|
|Ding, Yi; Fujimoto, L Miya; Yao, Yong et al. (2015) Solid-state NMR of the Yersinia pestis outer membrane protein Ail in lipid bilayer nanodiscs sedimented by ultracentrifugation. J Biomol NMR 61:275-86|
|Marassi, Francesca M; Ding, Yi; Schwieters, Charles D et al. (2015) Backbone structure of Yersinia pestis Ail determined in micelles by NMR-restrained simulated annealing with implicit membrane solvation. J Biomol NMR 63:59-65|