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Biochemie IV – Struktur und Dynamik von Biomolekülen II. (Mittwochs 8-10 h, INF 230, klHS)

Biochemie IV – Struktur und Dynamik von Biomolekülen II. (Mittwochs 8-10 h, INF 230, klHS) 30.4. Jeremy Smith: Intro to Molecular Dynamics Simulation. 7.5. Stefan Fischer: Molecular Modelling and Force Fields. 14.5. Matthias Ullmann: Current Themes in Biomolecular Simulation.

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Biochemie IV – Struktur und Dynamik von Biomolekülen II. (Mittwochs 8-10 h, INF 230, klHS)

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  1. Biochemie IV – Struktur und Dynamik von Biomolekülen II. (Mittwochs 8-10 h, INF 230, klHS) 30.4. Jeremy Smith: Intro to Molecular Dynamics Simulation. 7.5. Stefan Fischer: Molecular Modelling and Force Fields. 14.5. Matthias Ullmann: Current Themes in Biomolecular Simulation. 21.5. Ilme Schlichting: X-Ray Crystallography-recent advances (I). 28.5. Klaus Scheffzek: X-Ray Crystallography-recent advances (II). 4.6. Irmi Sinning: Case Study in Protein Structure. 11.6. Michael Sattler: NMR Applications in Structural Biology. 18.6. Jörg Langowski: Brownian motion basics. 25.6. Jörg Langowski: Single Molecule Spectroscopy. 2.7. Karsten Rippe: Scanning Force Microscopy. 9.7.Jörg Langowski: Single Molecule Mechanics. 16.7. Rasmus Schröder: Electron Microscopy. 23.7. Jeremy Smith: Biophysics, the Future, and a Party.

  2. Protein Computational Molecular Biophysics Universität Heidelberg

  3. IBM PLANS SUPERCOMPUTER THAT WORKS AT SPEED OF LIFE IBM today will announce its intention to invest $100 million over the next five years to build Blue Gene, a supercomputer that will be 500 times faster than current supercomputing technology. Researchers plan to use the supercomputer to simulate the natural biological process by which amino acids fold themselves into proteins. (New York Times 12/06/99)

  4. Exploring the Folding Landscape Protein Folding

  5. Uses of Molecular Dynamics Simulation: • structure • flexibility • solvent effects • chemical reactions • ion channels • thermodynamics (free energy changes, binding) • spectroscopy • NMR/crystallography

  6. Model System Atomic-Detail Computer Simulation Molecular Mechanics Potential Energy Surface Exploration by Simulation..

  7. Model System • set of atoms • explicit/implicit solvent • periodic boundary conditions • Potential Function • empirical • chemically intuitive • quick to calculate Tradeoff: simplicity (timescale) versus accuracy

  8. Lysozyme in explicit water

  9. 2/8 MM Energy Function f q l r q q j i

  10. Potential Function  Force Newton’s Law:

  11. Taylor expansion: Verlet’s Method

  12. 1 hour here Statistical Mechanics Observable Ensemble Average 1 hour here

  13. MD Simulation: Ergodic Hypothesis:

  14. Analysis of MD Configurations Averages Fluctuations Time Correlations

  15. Timescales. Bond vibrations - 1 fs Collective vibrations - 1 ps Conformational transitions - ps or longer Enzyme catalysis - microsecond/millisecond Ligand Binding - micro/millisecond Protein Folding - millisecond/second Molecular dynamics: Integration timestep - 1 femtosecond Set by fastest varying force. Accessible timescale about 10 nanoseconds.

  16. SOME EXAMPLES

  17. Does CD4-binding peptide have a similar structure in all strains of HIV-1 ? 11 Sequences in 9 clades • A1 LEU PRO CYS ARG ILE LYS GLN PHE ILE ASN MET TRP GLN GLU VAL +2 • B1 LEU PRO CYS ARG ILE LYS GLN ILE VAL ASN MET TRP GLN GLU VAL +2 • C1 ILE PRO CYS ARG ILE LYS GLN ILE ILE ASN MET TRP GLN GLU VAL +2 • D2 LEU PRO CYS ARG ILE LYS PRO ILE ILE ASN MET TRP GLN GLU VAL +2 • E2 LEU PRO CYS LYS ILE LYS GLN ILE ILE ASN MET TRP GLN GLY VAL +3 • E3 LEU PRO CYS LYS ILE LYS GLN ILE ILE LYS MET TRP GLN GLY VAL +4 • F1 LEU LEU CYS LYS ILE LYS GLN ILE VAL ASN LEU TRP GLN GLY VAL +2 • G2 LEU PRO CYS LYS ILE LYS GLN ILE VAL ARG MET TRP GLN ARG VAL +5 • 1A0 LEU PRO CYS LYS ILE LYS GLN ILE VAL ASN MET TRP GLN ARG VAL +4 • 2A3 LEU GLN CYS ARG ILE LYS GLN ILE VAL ASN MET TRP GLN LYS VAL +4 • OC4 ILE PRO CYS LYS ILE LYS GLN VAL VAL ARG SER TRP ILE ARG GLY +5

  18. Molecular Dynamics Simulation Setup • Box dimensions: 53x40x40 Ǻ • Explicit water molecules (TIP3P) (~8600 atoms) • Explicit ions (Sodium and Chloride, 26 ions in total); physiological salt: 0.23M • ~240 peptide atoms => approx. 8900 atoms in total • Uncharged system • NPT ensemble: 300K, 1atm • 5ns simulation time for each strain => 55ns total simulation time

  19. Dihedralangles  

  20. Surface electrostatic properties conserved.

  21. Cancer Biotechnology. Detection of Individual p53-Autoantibodies in Human Sera

  22. Rhodamine 6G

  23. Fluorescence Quenching of Dyes by Trytophan Quencher MR121 Dye

  24. Fluorescently labeled Peptide ?

  25. Analysis r

  26. Strategy: Healthy Person Serum Cancer Patient Serum Quenched Fluorescent Results:

  27. Protein Folding/Unfolding

  28. Exploring the Folding Landscape Protein Folding

  29. Prion diseases of animal and man BSE cattle bovine spongiform encephalopathy scrapie sheep CWD elk chronic wasting disease TME mink transmissible mink encephalopathy kuru humanCJD human Creutzfeldt-Jakob disease sporadic genetic infectiousvCJD human variant CJDGSS human Gerstmann-Sträussler-Scheinker diseaseFFI human fatal familial insomnia

  30. Properties of the prion protein • The natural prion protein is encoded by a single exon as a polypeptide chain of about 250 to 260 amino acid residues. • Posttranslational modification: cleavage of a 22 (N-terminal) and 23 (C-terminal) residue signal sequence => about 210 amino acid residues • PrP contains a single disulfide bridge. • PrP contains 2 glycosylation sites. • PrP inserts into the cellular plasma membrane through a glycosyl-phosphatidyl-inositol anchor at the C-terminus.

  31. Structure of the prion protein

  32. Superimposed PrP structures The first image below shows the structure of part of the hamster and mouse PrPC molecules superimposed. The close similarity in the structures is obvious, as is the preponderance of alpha helical structure.

  33. Location of human mutations The picture shows the position of various mutations important for prion disease development in humans modelled on the hamster structure PrPC. Many of these mutations are positioned such that they could disrupt the secondary structure of the molecule.

  34. Mouse Prion Protein (PrPc) NMR Structure

  35. Structure of PrPSc The PrPSc has a much higher b-sheet content.

  36. Bundeshochleistungsrechner Hitachi SR8000-F1

  37. IBM PLANS SUPERCOMPUTER THAT WORKS AT SPEED OF LIFE IBM today will announce its intention to invest $100 million over the next five years to build Blue Gene, a supercomputer that will be 500 times faster than current supercomputing technology. Researchers plan to use the supercomputer to simulate the natural biological process by which amino acids fold themselves into proteins. (New York Times 12/06/99)

  38. Safety in Numbers

  39. Large-Scale Conformational Change

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