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Proteins are dynamic systems

Proteins are dynamic systems. Concerted motions of the p53 binding domain of MDM2. protein dynamics: Timescale: from s to fs. Inhomogeneity within same structure. Conformational substates Temperature dependence. Motions of tyrosine kinase. Observation of protein dynamics.

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Proteins are dynamic systems

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  1. Proteins are dynamic systems Concerted motions of the p53 binding domain of MDM2

  2. protein dynamics: • Timescale: from s to fs. • Inhomogeneity within same structure. • Conformational substates • Temperature dependence. Motions of tyrosine kinase

  3. Observation of protein dynamics • Mössbauer spectroscopy: based on the interaction between x-ray (e. g. synchrotron radiation) and atomic nucleus in solids or some liquids (nuclear resonance scattering). Lamb-Mössbauer factor f:

  4. Incoherent neutron scattering:

  5. Experimental observation • Linear up to about Tc=180K. • T>Tc: a dramatic increase of the slope  new modes of motion contribute to MSD, even in dry Mb. • This phenomenon has been found in a large number of proteins. Data from incoherent neutron scattering (open symbols), and Mössbauer absorption (full symbols) with different Mb-crystals.

  6. Experimental observation How fast are these new modes of motion? • Consider the relation of energy and time resolution: The new protein specific motions (T>Tc) occur on a timesacle < 4ps! Symbols: data from several Mössbauer experiments "—": calculated data from phonon density.

  7. Example: photosystem II of spinach Average mean square displacements of iron in photosystem II of spinach (•) and efficiency of the electron transfer from quinone A to quinone B as a function of temperature.

  8. Proteins and glasses • Glasses are better studied and much simpler than proteins, so they can serve as guides to formulate concepts and theories for proteins.

  9. SiO2 glass SiO2crystal Glass transition • Unlike crystalline solids, glasses do not have a certain melting temperature. • The viscosity changes gradually with increasing temperature. • Glass transition temperature Tg: At which the viscosity of a material reaches 10^13p = poise (=0.1kg/ms).

  10. Glass transition Energy landscape • T<Tg: „Frozen“ in one of many local minima, very little mobility. • T>Tg: The energy barriers can be overcome and other local minima explored.

  11. Glass-like transition in proteins • Proteins also possess a glass transition temperature Tg: • Near Tg: Dynamical transition to a glass-like solid, • T<Tg: Quenched anharmonic motions and long-range correlated motion. (functionally relevant motions) • From computer simulations:Glassy behaviour of solvent drives the transition of protein.

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

  13. Mountain Landscape Energy Landscapes

  14. More realistic pictures of energy landscapes

  15. Dynamical TransitionMean-Square Displacement Nonlinear in T

  16. Onset of Protein Function n n d d The Protein Glass Transition Liquid Glass Harmonic

  17. VALERIE REAT RACHEL DUNN ROY DANIEL JOHN FINNEY Dynamics & Activity of Glutamate Dehydrogenasein a Cryosolvent[70% MeOD; 30%; D2O] .

  18. 7500 ALEX TOURNIER Principal Component Analysis of the Myoglobin Glass Transition

  19. ALEX TOURNIER Normal Mode Frequency, N N P Principal Mode Frequency, P Anharmonicity Factor = N/ P

  20. Error in Gaussian Fit P(r) Good Fit P(r) Bad Fit

  21. Free Energy Profiles of Dominant Principal Components

  22. Mode Incipient at Myoglobin Glass Transition

  23. Low temperature onset of anharmonic dynamics Methyl dynamic heterogeneity • Simulation details : • Hydrated Myoglobin crystal • 10 ns MD trajectory (NPT) • Methyl dynamics at 150 K Role of Xenon cavities Mean Square Displacement Site-specific spectral analysis • Mobile CH3 groups are populated near xenon cavities • Protein dynamical transition~220K • Onset of anharmonic dynamics~150K • Low frequency methyl dynamics is sensitive to local packing

  24. KRZYSZTOF KUCZERA MARTIN KARPLUS Dynamical Transition in an Isolated Protein: MD Simulation of Myoglobin.

  25. 5 4 3 2 1 JIANCONG XU ALEX TOURNIER Radial Dependence of Dynamical Transition Hydrated Myoglobin 1 2 3 4 5

  26. System System Prot Prot Solv. Solv. 1st Heatbath Heatbaths 2nd Heatbath Nose-Hoover-Chain Multiple Heatbath Simulation Algorithm Canonical Distribution of Temperatures

  27. T1 T2 KEEP COLD VARY T ALEX TOURNIER DUAL HEAT-BATH SIMULATIONS e.g.

  28. ALEX TOURNIER Translation Translation Water Diffusion on a Protein Surface Rotation

  29. Water Translational Diffusion Protein Fluctuations Protein Rotation ALEX TOURNIER Water Diffusion and the Glass Transition

  30. JENNIFER HAYWARD Effect of Approximations in Experimental Neutron Scattering Data Analysis u2 1 ns ‘Low’-q (0q2 1.44Å-2) perfect resolution Low-q, 20 eV resolution ‘High’-q, (0q2 23Å-2),20 eV resolution Harmonic

  31. FIT RIGID REFERENCE STRUCTURES TO EACH FRAME OF FULLY-FLEXIBLE TRAJECTORY TRAJECTORY OF RIGID BODIES GERALD KNELLER

  32. 6 6 5 4 3 2 1 SERGE DELLERUE, ANDREI PETRESCU, MARIE-CLAIRE BELLISSENT-FUNEL Atomic Dynamics as a function of Distance from Protein Centre Concentric Shells

  33. A 1.0 0.8 0.6 I(q,t) 0.4 0.2 0.0 10-1 100 101 102 103 t (ps) B 1.0 0.8 0.6 I(q,t) 0.4 0.2 0.0 10-1 100 101 102 103 t (ps) Derivation of Simplified Dynamical Description from Molecular Dynamics Simulation Data: Fit of a Stretched Exponential Model to the Intermediate Scattering Function.

  34. Radially-Softening Dynamical Model Atom in Sphere Rav= radius of sphere in which atom diffuses.  = dynamical correlation time  = stretch factor (range of timescales spanned)

  35. Some “Predictions” for the Spallation Neutron Source….

  36. LARS MEINHOLD PROTEIN THE FREQUENCIES AFFECTED WATER Pressure Transition in Protein Dynamics Crystalline Staphylococcal Nuclease

  37. MSD: DoS: r(t+t) t r(t) protein PMF: mode 5 mode 100 mode 1 mode 30 solvent Pressure-induced transition in protein dynamics Meinhold, Smith. PRE 72:061908 (2005)

  38. Protein:Protein Interactions.Vibrations at 150K VANDANA KURKAL-SIEBERT

  39. GERALD KNELLER FIT RIGID REFERENCE STRUCTURES TO EACH FRAME OF FULLY-FLEXIBLE TRAJECTORY TRAJECTORY OF RIGID BODIES

  40. STÉPHANIE HÉRY DANIEL GENEST SVEN LAMMERS Scattering of X-Rays by Protein Crystals Real Crystal Ideal Crystal + Perturbations =

  41. Dynamics Collective Motions PROTEIN FUNCTION Structure phase problem Diff. Scatt. (B factors) X-ray rel(r) Bragg detector beam DIFFUSE Scattering disorder static - dynamic CORRELATION NMR (13%) X-ray (87%)

  42. STÉPHANIE HÉRY DANIEL GENEST Molecular Dynamics of Lysozyme Unit Cell Full Trajectory Experimental Rigid-Body Decomposition Rigid-Body Fit (R-factor re: Full Trajectory = 5.3%)

  43. LARS MEINHOLD X-Ray Diffuse Scattering Staphylococcal Nuclease

  44. Staph nuclease S Gruner et al still exposure diffuse scattering after removal of Bragg peaks

  45. Staph nuclease S Gruner et al h k l

  46. MD simulations • unit cell: 15993 atoms • 4 proteins • 2115 TIP3P + 48 Cl- • CHARMM(param:22) • PME • Nose-Hoover (300K,1bar) • 4 X10ns, Dt =1fs data reduction 3D – 2D – 1D Interpreting the experimental data …

  47. S.LAMMERS Unit cell of Staphylococcal nuclease Space group P41 (4 proteins) Water box with unit cell dimensions (1972 molecules) 36 chloride ions Total number of atoms 15540

  48. Intensity in hk0 plane Experimental intensity distribution Theoretical intensity distribution

  49. Scattering vector in hk0 plane

  50. Intensity in hk0 plane 2500 frames 25 frames 12000 frames 250 frames

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