Collaborative research: CIBR: Computational resources for modeling and analysis of realistic cell membranes

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Biological membranes are semi-permeable barriers that separate living cells from the environment and create intracellular compartments. They are composed of many types of lipids and are crowded with numerous transmembrane and peripheral membrane proteins. These proteins participate in all vital cellular processes, including biogenesis, energy and signal transduction, molecular transport, vesicular trafficking, cell motility, recognition, adhesion, and shape regulation. Despite the growing number of atomic structures of membrane proteins, the lack of information about their spatial positions and protein-lipid interactions in their native membranes impedes our understanding of molecular mechanisms of their folding, stability, function, and regulation. Motivated by rising demands in realistic representation of proteins in non-planar and deformable membranes with natural lipid compositions, we propose a creation of a high-capacity cyberinfrastructure for fast and reproducible assembly of membrane proteins with natural lipids to build flexible multicomponent biomembranes for subsequent structural analysis and molecular dynamics (MD) simulations. This project will promote synergy between scientific research and education by training computer science students in developing bioinformatics resources, by using the developed toolbox for teaching, and by providing training materials and web-based workshops for students and the user community to promote research experience in membrane simulations.This collaborative project will enhance and combine capabilities of the highly recognized and widely used PPM/OPM and CHARMM-GUI resources that have been developed by the research teams from the University of Michigan and Lehigh University. The project has three main components. First, the PPM (Positioning of Proteins in Membranes) method will be advanced for calculating the spatial arrangement and binding energy of proteins in deformable membranes characterized by diverse polarity profiles, asymmetry, charge, and curvature. Second, a new PPM/CHARMM-GUI toolbox will be developed by integrating the improved PPM method and CHARMM-GUI Membrane Builder to assemble native-like protein-lipid systems and provide input files for realistic simulations of biomembranes by various MD simulation packages. The open web-based platform will allow users of diverse expertise to easily setup and perform simulations of membrane proteins with known three-dimensional (3D) structures in deformable membranes with complex lipid composition. Third, native-like all-atom membrane systems for thousands of known membrane protein structures with natural lipids from eukaryotic and prokaryotic cells and organelles will be produced using this toolbox. The generated protein-lipid systems together with the inputs for MD simulations will be deposited in the improved and expanded OPM database (at opm.phar.umich.edu). These inputs can be directly used for state-of-the-art MD simulations of realistic cell membranes to assist in planning and interpreting experimental studies. The proposed toolbox (at charmm-gui.org) will significantly enhance the capacity of existing web resources for biomolecular simulations, while ensuring the long-awaited transition from modeling only transmembrane proteins to simulations of both transmembrane and peripheral proteins and their complexes in membranes; from artificial lipidThis award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.