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. Proteins from the BAR domain superfamily [1], ubiquitous in many organisms andcell types (www.ks.uiuc.edu/Research/BAR-domain), are implicated in amultitude of cellular processes involving membrane remodeling, e.g., endocytosis,apoptosis, and cell-cell fusion. In vitro, these proteins sculpt high-curvature membranetubes and vesicles [2, 3] from low-curvature liposomes. BAR domains formbanana-shaped homodimers bearing a high density of positively charged residueson the concave surface [4?6], which facilitates sculpting of negatively charged membranes.However, single BAR domains induce only local membrane curvature [7, 8],while recent cryo-EM reconstructions [3] reveal that sculpting of membrane tubesand vesicles is performed by many BAR domains arranged in lattice-like scaffolds.Despite extensive studies, the dynamics of membrane sculpting by multiple BARdomains working in concert remains unresolved. It also remains unclear how BARdomain lattices are formed and maintained, and how various lattice types determinethe curvature of the underlying membrane. Beyond understanding BAR domainsalone, answering these questions is crucial for rendering a molecular-level picture ofmembrane remodeling in cells in general, since the mechanisms utilized by BAR domainsare used elsewhere as well. MD simulations are well suited to study dynamicsof membrane sculpting at the molecular level, but, since multiple proteins interactingsimultaneously with large membrane surfaces needs to be described, all-atomMD simulations of BAR domain lattices are extremely demanding. Investigatingeven a small BAR domain lattice requires a simulation of a multi-million atom system over hundreds of nanoseconds, while studying membrane tubulation involves simulation of a 100 million-atom system for hundreds of microseconds. Thus, this project poses a computational challenge, requiring massive all-atom MD simulations and coarse-grained modeling done in concert, i.e., a multiscale approach.Resource scientists have developed models describing membrane sculpting by BARdomains at four levels of resolution [8], employing all-atom molecular dynamics,residue-based coarse graining (RBCG) that resolves single amino acids and lipidmolecules, shape-based coarse graining (SBCG) that resolves overall protein andmembrane shapes, and a continuum elastic membrane model. The four-scale simulationssampled many BAR domain lattice types and elucidated how the membranecurvature generated depends on the lattice type [8, 9]. Formation of entire membranetubes by lattices of BAR domains over time scales of 200 microseconds wasobserved in SBCG simulations, and an all-atom simulation of a 2.3 million atomsystem covering 0.3 microsecond probed the dynamics of one chosen BAR domainlattice in atomic detail [9]. The lattice arrangements found to be optimal for producinghigh membrane curvature are composed of protein rows separated by 5 nm,the stability of the rows being maintained through electrostatic interactions betweenBAR domains, and bending arising due to the concerted scaffolding of the membraneby the concave surface of the proteins. Thus, a molecular mechanism for thecell-scale action of BAR domain is emerging from the computational studies [8, 9].The BAR domain studies constitute a major driving project in the structural systemsbiology core of the Resource. The computational challenges inherent to theproject drive the advancement of multi-million atom simulations as well as multiscalemodeling. The tools developed are indispensable for modeling of other processesoccurring at the sub-cellular scale, and as such contribute to the long-termeffort of the Resource towards creating the framework for modeling of whole-cell atthe molecular level.BIBIOGRAPHY[1] G. Ren, P. Vajjhala, J. S. Lee, B. Winsor, and A. L. Munn. The BAR domain proteins:Molding membranes in fission, fusion, and phagy. Microbiology and molecular biologyreviews, 70:37?120, 2006.[2] K. Takei, V. I. Slepnev, V. Haucke, and P. De Camilli. Functional partnership betweenamphiphysin and dynamin in clathrin-mediated endocytosis. Nat. Cell Biol., 1:33?39,1999.[3] A. Frost, R. Perera, A. Roux, K. Spasov, O. Destaing, E. H. Egelman, P. De Camilli,and V. M. Unger. Structural basis of membrane invagination by F-BAR domains.Cell, 132:807?817, 2008.[4] B. J. Peter, H. M. Kent, I. G. Mills, Y. Vallis, P. J. G. Butler, P. R. Evans, and H. T.McMahon. BAR domains as sensors of membrane curvature: The amphiphysin BARstructure. Science, 303:495?499, 2004.[5] W. M. Henne, H. M. Kent, M. G. J. Ford, B. G. Hegde, O. Daumke, P. J. G. Butler,R. Mittal, R. Langen, P. R. Evans, and H. T. McMahon. Structure and Analysisof FCHo2 F-BAR Domain: A Dimerizing and Membrane Recruitment Module thatEffects Membrane Curvature. Structure, 15:1?14, 2007.[6] A. Shimada, H. Niwa, K. Tsujita, S. Suetsugu, K. Nitta, K. Hanawa-Suetsugu,R. Akasaka, Y. Nishino, M. Toyama, L. Chen, Z. Liu, B. Wang, M. Yamamoto,T. Terada, A. Miyazawa, A. Tanaka, S. Sugano, M. Shirouzu, K. Nagayama, T. Takenawa,and S. Yokoyama. Curved EFC/F-BAR-domain dimers are joined end to endinto a filament for membrane invagination in endocytosis. Cell, 129:761?772, 2007.[7] P. D. Blood and G. A. Voth. Direct observation of Bin/amphiphysin/Rvs (BAR)domain-induced membrane curvature by means of molecular dynamics simulations.Proc. Natl. Acad. Sci. USA, 103:15068?15072, 2006.[8] A. Arkhipov, Y. Yin, and K. Schulten. Four-scale description of membrane sculptingby BAR domains. Biophys. J., 95:2806?2821, 2008.[9] Y. Yin, A. Arkhipov, and K. Schulten. Simulations of membrane tubulation by latticesof amphiphysin N-BAR domains. Structure, 2009. In press.
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