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Car-Parrinello Molecular Dynamics Simulations (CPMD): Applications

Car-Parrinello Molecular Dynamics Simulations (CPMD): Applications. Ursula Rothlisberger EPFL Lausanne, Switzerland. DNA-Repair: Endonuclease IV. Anti-AIDS: HIV-1 Protease. Molecular Mechanisms of Apoptosis:Caspase-3. Prions and Metal Ions. Photoisomerization in Rhodopsin.

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Car-Parrinello Molecular Dynamics Simulations (CPMD): Applications

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  1. Car-Parrinello Molecular Dynamics Simulations (CPMD): Applications Ursula Rothlisberger EPFL Lausanne, Switzerland

  2. DNA-Repair: Endonuclease IV Anti-AIDS: HIV-1 Protease Molecular Mechanisms of Apoptosis:Caspase-3 Prions and Metal Ions Photoisomerization in Rhodopsin Galactose Oxidase

  3. Electronic Structure Effects in Biology • enzymatic reactions • low-barrier H-bonds • most stable protomers • force field parameterization for • ‘exotic’ molecules • many-body interactions: polarization effects • (transition) metal ions • electronic properties: Electronic excitation energies chemical shifts etc.

  4. Enzymes at work... Shanghai Crab

  5. Gly27’ Asp25 Asp25’ Gly27 Thr26’ Thr26 HIV- Virus (AIDS) HIV- I Protease

  6. HIV-1 PR HIV-PR is essential for the formation of infective viral forms Immature non-infective viral particles Infective viruses

  7. Viewing enzymes in action... HIV- I Protease

  8. Viewing Enzymes in Action: Caspase-3 Cys285 His237 DEVD M. Sulpizi, A. Laio, J. VandeVondele, A. Cattaneo, P. Carloni, and U.R., Proteins 52, 212 (2003)

  9. Viewing Enzymes in Action: Caspase-3 Free Energy Profile: 20 kcal/mol M. Sulpizi, A. Laio, J. VandeVondele, A. Cattaneo, P. Carloni, and U.R., Proteins 52, 212 (2003)

  10. Catalytic Reactions Ep Transition State catalyzed reaction reactants products rc

  11. RationalDesignof Biomimetics R3 = SPh, SPr , Bu , Br t R5 = Bu , Br R- H2 C - OH + O2 R-C + H2O2 O = \ H Galactose Oxidase Synthetic Compound t i U.R, K.Doclo, P. Carloni, M. Parrinello, JBIC 5, 236 (2000)

  12. QM/MM Simulations of KcsA L. Guidoni, V. Torre, P. Carloni – Biochemistry, 38, 8599-8604 1999 → High Electrostatic Field with large Fluctuations Polarization Effects?? ~20’000 atoms / 80 A3 box Octane/water slab as membrane mimetic environment

  13. Attribution of the Glu71/Asp80 Protonation state

  14. 12 ps of QM/MM simulation at 100 K

  15. The Glu-71 protonated structure is closer to the x-rays

  16. Probability distribution of finding the proton (100K) Approximate energy surface

  17. Induced polarization effects are expected to be important on the ligands O Gas phase model

  18. Preliminary QM/MM Test case: the S3 Pocket Density difference plots Small QM/MM system (S3) with hydrogen capping

  19. Induced polarization on the carbonyls is missing in the force field description

  20. Cis/Trans Photoisomerization in Rhodopsin: The First Steps in Vision 200fs 0.67

  21. Photocycle

  22. 10ns Classical MD Simulations PDB: 1HZX (Teller et al. 2001) total # of atoms: 24000  RMS backbone: 0.9Å

  23. QM/MM Simulations of Intermediates cis

  24. Excited State Photoisomerization

  25. 2 1 3 4 RMSD: 0.36 Å Classic ROKS Isomerization Trials ROKS, 1200 K, 290 fs Classical MD, 150 fs U. F. Röhrig, L. Guidoni, A. Laio, I. Frank, U. Röthlisberger, submitted

  26. Classical Isomerization Studies cis trans U. Röhrig, L. Guidoni, and U. Rothlisberger, Biochemistry 41, 10799 (2002)

  27. A Molecular Spring for Vision cis trans U. Röhrig, L. Guidoni, and U. Rothlisberger, Biochemistry 41, 10799 (2002)

  28. 11-cis Comparison to X-linking Data all-trans 1HZX all-trans Borhan et al., Science 288, 2209 (2000)

  29. Strain Propagation U. Röhrig, L. Guidoni, and U. Rothlisberger, Biochemistry 41, 10799 (2002)

  30. ΔEex S1 S0 RHO Spectra of the Intermediates S2,3,4 Iso1 HOMO/LUMO Gap Exp. Iso2 S1 Iso3

  31. steric influence of the protein binding pocket determines absorption energy electrostatic influence of the protein environment induces a constant shift Spectral Shift Gas Phase/Protein TD-LR-DFT Excitation Energies of Snapshots from a QM/MM S0 Simulation

  32. 2.34 eV 2.43 eV Photocycle 2.24 eV ? 2.30 eV Assumption: TDDFT systematically red shifted by 0.2 eV

  33. Fatal Neurodegenerative • Diseases: • Mad Cow Disease (BSE) • Scrapie • Creutzfeldt-Jakob • caused by abnormal • isoform PrP(Sc) Prion Proteinsand Metal Ions http:\\ www.mad-cow.org Human Prion Protein (Wuthrich et al. PNAS 97, 145 (2000))

  34. Complex1 Complex 3 Complex 2 His 187 pH His 140 Complex 1 : 4O Complex 2 : 1N3O / 1N2O1S Histidine N Non-ex. proton Complex 3 : > 1N (backbone?) His 177 New experimental evidence (EPR): Cu2+ binds in structured part In Collaboration with S. van Doorslaer, G. Cereghetti,A. Schweiger and R. Glockshuber, ETH Zurich, Switzerland

  35. Cu-coordinated Natural abundance S 19.1% N 58.3% O 22.6% Localization of Possible Binding Sites via a Parallel Statistical and QM Approach • 111 PDB structures  2.0 Å resolution • 216 copper binding sites • 928 donor atoms

  36. His 140 His 140 Asp 144 Asp 147 Asp 147 Met 138 R = 12 R = 21 Tyr 157 Tyr 128 Met 206 Met 206 Tyr 155 Asp 178 Met 213 His 177 His 187 His 187 R = 24 R = 20 R = 20 Set of Candidate Structures

  37. QM/MM Car-Parrinello Simulations Dynamical Ligand Exchange Active Site Proton Transfer His 140 Cu2+ Asp 144 Asp 147

  38. QM/MM Car-Parrinello Simulations Dynamical Ligand Exchange Active Site Proton Transfer His 140 Cu2+ Asp 144 Asp 147

  39. Asp 144 His 140 Cu2+ Asp 147 Connection with Experiment - calculation of hyperfine coupling constants  EPR experiments  site-directed mutagenesis experiments

  40. Hyperfine Coupling Constants Binding Site H187 (PB86, QZ4P)

  41. Rational Design of Radiopharmaceuticals: 99mTc radiolabelled glucose • 99mTc has nearly ideal physical properties and availability • ~90% of diagnostic studies are carried out with 99mTc • natural substrate of hexokinase (glucose) is used as the targeting moiety • A structural and electronic characterization of radiolabeled glucose was performed, in aqueous solution (QM/MM), as well as in the gas phase

  42. DFT Consistent Force Fields via Force Matching (Patrick and Alessandro) • qi’s via D - RESP procedure • adjust other terms via force matching: • Gly-Ala in water • H2PO4- in water • automatic generation of force fields for exotic compounds • long time propagation • new DFT-force field? Polarizable? vdW(q)?

  43. “Variational” D-RESP charges - charges due to the electronic charge distribution are fitted to the electrostatic field V on the MM atoms (j  NN): Harmonic restraint Hirshfeld charge  optimal point charge set in realistic environment  chemical descriptors  measure for importance polarization effects  analytic gradients with respect to ionic position and density  exclusion rules, electrostatic coupling in intermediate range  electronic constraints A. Laio, J. VandeVondele, U.R. J. Phys. Chem. B 106, 7300 (2002.)

  44. Consistency of QM and MM Electrostatics • Standard Deviation of the • Electrostatic Field: Gly-Ala in Water (SPC), 10ps, 300K Field: Dipole Moment: AMBER95: 6-13 % GROMOS96: 9-16 % D-RESP: 6-8 % D-RESP(pol): 5 % AMBER95: 6 % GROMOS96: 7 % D-RESP: 3 % D-RESP(pol): 2 %

  45. Ab initio Cispt docking onto DNA

  46. A piano chair to fight cancer Prof. Dyson’s group found biologically interesting compound when searching for hydrogenation catalysts: [Ru(η6-p-cymene)Cl2(pta)](pta=1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane) Chem. Commun 2001, 1396

  47. p-cymRuPTA: No space to move; DNA steps back Initialstructure 750ps 750ps Thick CPK for RAPTA: Initial structure after 200 steps of minimization (all atoms) Lines: after 100ps equilibration of RAPTAThin CPK: after 750ps of free equilibration of all atoms

  48. Collaborations • Michele ParrinelloETH Zurich, Switzerland • Carla MolteniUniversity of Cambridge, UK • Irmgard FrankUniversity of Munich, Germany • Jürg HutterUniversity of Zurich, Switzerland • Paolo CarloniSISSA, Trieste, Italy

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