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PUMP kin

Centre for Membrane Pumps in Cells and Disease. Dynamics of Multi-Domain Proteins. Going from an All-Atom Representation to a Protein-Domain Representation.

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PUMP kin

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  1. Centre for Membrane Pumps in Cells and Disease Dynamics of Multi-Domain Proteins Going from an All-Atom Representation to a Protein-Domain Representation • IWONA SIUDA1,2,3, CHRISTIAN N. S. PEDERSEN1,3, LEATHØGERSEN1,2,31Centre for Membrane Pumps in Cells and Disease, Danish National Research Foundation, Denmark • 2Bioinformatics Research Centre, C. F. MøllersAllé 8, DK-8000 Aarhus C, Denmark3Department of Molecular Biology, Aarhus University, Gustav WiedsVej 10C, DK-8000 Aarhus C, Denmark Test Set ThedomELNEDIN Model • Test set withprotein structuresresolved for at least two conformations. • RMSD between same domains in different conformations is on average 1.1 ± 0.3 Å. • Thus, it seems fair to restrain internal domain dynamics while modeling domain movements. 1USG 1USK 1AMA 9AAT • Molecular dynamics modeling is highly valuable as a test ground for hypotheses in close interplay with wet-lab experiments. • Models with atomic resolution suffer from hard time scale limitations, but are very well established. • Models with residue resolution access the microsecond time scale1,2, but suffer from artificial restrictions to the structure and dynamics3. • The domELNEDIN model maintains the residue resolution, but restrictions are released to allow for domain movements. 3EZA 2EZA 1L5E 1L5B 1HVU 2HMI 1CTS 4CTS 1E88 1E8B 1B47 2CBL Coarse Grained Representations New Model EstablishedModels All Atom (AA) Model domELNEDIN Model AA Model ELNEDIN Model CG Model Periplasmic Leucine-Binding Protein pdb: 1USG + Mapping atoms into beads • Residue details • Time scale≈ 1 μs • Residue details • Time scale≈ 1 μs • Structure stable • Conformational changes allowed • Residue details • Time scale≈ 1 μs • Structure stable • Atomic details Coarse Grained (CG) Model ÷ • Conformational changes not allowed • Time scale≈ 100 ns • Structure collapse Adding elastic network Inside domains only Overall The Pump Perspective • The P-type ATPases consist of well defined protein domains. For the sarcoplasmic reticulum Ca2+-ATPase (SERCA), structures have been solved for several conformations. • SERCA is therefore a unique test case for the application of the domELNEDIN model to membrane proteins in general and to ATPase pumps in particular. SERCA Structures Ca2E1~P-ADP pdb1T5S ELNEDIN Model domELNEDINModel • With domELNEDIN molecular dynamics simulations of the ATPases, we would be able to model hypotheses involving conformational changes, which is currently not possible. References 1 Marrink et al., J. Phys. Chem. B,2007, 111, 7812–7824 2 Monticelli et al., J. Chem. Theory Comput. 2008, 4, 819–834 3 Periole et al., J. Chem. Theory Comput. 2009, 5, 2531-2543 E2P pdb3B9B E2-ATP pdb2C88 www.pumpkin.au.dk PUMPkin Bioinformatics Research Centre | C. F. MøllersAllé 8 | DK-8000 Aarhus C | Denmark

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