1. PUMPkin C ENTRE FOR M EMBRANE P UMPS IN C ELLS AND D ISEASE www.pumpkin.au.dk Dynamics of Multi-Domain Proteins Going from an All-Atom Representation to a Protein-Domain Representation 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 IWONA SIUDA 1,2,3, CHRISTIAN N. S. PEDERSEN 1,3, LEA THØGERSEN 1,2,3 1 Centre for Membrane Pumps in Cells and Disease, Danish National Research Foundation, Denmark 2 Bioinformatics Research Centre, C. F. Møllers Allé 8, DK-8000 Aarhus C, Denmark 3 Department of Molecular Biology, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark Bioinformatics Research Centre | C. F. Møllers Allé 8 | DK-8000 Aarhus C | Denmark Test Set 9AAT 1AMA 1USK 1USG 1L5B 1L5E 2EZA 3EZA 1B47 2CBL 4CTS 1CTS 1E8B 1E88 2HMI 1HVU PDB RMSD [Å] Domain average RMSD[Å] 1USK1USG7.04 0.68 1AMA9AAT1.66 0.98 4CTS1CTS2.37 1.38 1E8B1E882.79 1.14 2EZA3EZA1.86 1.15 1L5B1L5E6.51 1.09 1B472CBL1.87 0.54 2HMI1HVU5.73 1.41 The Pump Perspective The domELNEDIN Model ELNEDIN Model domELNEDIN Model CG Model AA Model Atomic details Time scale ≈ 100 ns Residue details Time scale ≈ 1 μ s Structure collapse Residue details Time scale ≈ 1 μ s Structure stable Residue details Time scale ≈ 1 μ s Structure stable Conformational changes allowed Conformational changes not allowed Established Models New Model ÷ + Coarse Grained Representations All Atom (AA) Model Adding elastic network Coarse Grained (CG) Model Mapping atoms into beads ELNEDIN ModeldomELNEDIN Model Overall Inside domains only Periplasmic Leucine-Binding Protein pdb: 1USG Test set with protein structures resolved 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. 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 scale 1,2, but suffer from artificial restrictions to the structure and dynamics 3. The domELNEDIN model maintains the residue resolution, but restrictions are released to allow for domain movements. PDB RMSD [Å] Domain average RMSD[Å] 1T5S2C8810.2 2.0 (1.1) 1T5S3B9B11.3 1.7 (0.8) 2C883B9B 6.4 1.7 (1.1) E2-ATP pdb 2C88 Ca 2 E1~P-ADP pdb 1T5S E2P pdb 3B9B The P-type ATPases consist of well defined protein domains. For the sarcoplasmic reticulum Ca 2+ -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 With domELNEDIN molecular dynamics simulations of the ATPases, we would be able to model hypotheses involving conformational changes, which is currently not possible.