1. Molecular Dynamics of Antimicrobial Peptides Interacting with Membrane Assoc. Prof. Lea Thøgersen Bioinformatic Research Centre Aarhus University DanCARD spring meeting, May 16, 2012

2. 20 aa antimicrobial peptide - peptaibol. No charged amino acids!! (one glutamate - probably protonated) Known to insert with N-terminus first Alamethicin Gln7 Glu18 Gln19 Tieleman, Berendsen, Sansom; Voltage-Dependent Insertion of Alamethicin at Phospholipid/Water and Octane/Water Interfaces. Biophys. J. (2001) 80 331

3. Coarse-Grained versus Atomistic MD Atomistic MD: time step of 1-2 fs, time frame sampled ~ 100 ns Coarse-grained MD: time step of 20-50 fs, time frame sampled ~ 1-10 μs Coarse-graining Reverse Coarse-graining PC lipid Alamethicin

4. 32 ns 7 ns Alamethicin Behavior 120 ns Alamethicin Hydrophilic side chains Lipid Head group Apolar tails C-term N-term Water Not shown

5. Peptide Aggregation 0-1 μs Top-view Schematic Side-view

6. Structure of the Aggregates 0 0.5 1 Gln7 Interaction with other peptides

7. Membrane Leakage 35-40 ns

8. Anoplin Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu 14 peptides: 7 in helix conformation (NMR structure from AAU) 7 in extended conformation in solution or on membrane surface as monomers or dimers

9. Analog Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu

10. Peptide Interactions Water Peptide Lipid Water Peptide Lipid ~3 peptides/aggregate Averaged over the 14 peptides in the ensemble. ~2 peptides/aggregate AnoplinAnalog

11. Forcing an entrance? AnoplinAnalog Tension => Membrane curvature

12. Acknowledgements Emad Tajkhorshid & the NAMD people Beckman Institute University of Illinois at Urbana-Champaign, USA Birgit Schiøtt & the Biomodelling Group Department of Chemistry University of Aarhus, Denmark Niels Christian Nielsen & Thomas Vosegaard Laboratory for Biomolecular NMR spectroscopy Department of Chemistry University of Aarhus, Denmark Funding: Jens Kristian Munk KU-Life University of Copenhagen