1. Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition? Structure of Protein Hydration Water Relevance of Transition to Function? Proton Transfer in Bacteriorhodopsin Minimum Energy Pathways, Attraction Basins and Convergence Channels Chloride Pumping in Halorhodopsin Large-Scale Conformational Change, - Annexin, Ras and Myosin Ligand Binding - Dynamics and Thermodynamics Lecture I: Physics Lecture II: Chemistry

2. Biomolecular Simulation - Basic Principles Molecular Mechanics Potential Model System QM MM For Reactions: Molecular Mechanics (MM) /Quantum Mechanics (QM) Energy Landscape: Explore by Simulation

3. Molecular Dynamics Simulation Experiment Simplified Description

4. Calculating Measurable Quantities from MD Many measurable quantities from one MD simulation in absence of experimental probe (e.g. NMR, fluorescence, IR, neutron, X-rays, ….) Time average over one molecule  Ensemble average.

5. Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition? Structure of Protein Hydration Water Relevance to Function?

6. X-Ray and Neutron Scattering Experiments: European Synchrotron Radiation Facility, Institut Laue-Langevin.

7. SCATTERING OF NEUTRONS AND X-RAYS kiki k i - k f = q hω ENERGY TRANSFER hq MOMENTUM TRANSFER kfkf COHERENT INCOHERENT SCATTERING g (r,t) g s (r,t) Elastic Quasielastic Inelastic Energy transfer, ω Δω e Δω qe Dynamic structure factor O r,t  S (q,ω) = e i(ωt-q·r) g(r,t) dr dt QUASIELASTIC DIFFUSIVE MOTIONS INELASTIC VIBRATIONAL COHERENT INCOHERENT STRUCTURAL FT [ g s (r,  )] NUCLEAR PROB. DISTRIBUTION ELASTIC

8. Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition? Structure of Protein Hydration Water Relevance to Function?

9. Lysozyme in explicit water FRANCI MERZEL

10. Low q : Size Radius of Gyration (R g ) Include Higher q : Chain Configurational Statistics q(Å -1 ) P(q) Small Angle Neutron Scattering

11. Geometric R g from MD simulation = 14.1  0.1Å SMALL-ANGLE SCATTERING RADII OF GYRATION

12.  o (d)-  (d) = Perturbation from Bulk  o (d)  10% increase  5% increase Radial Water Density Profiles Protein Water  (d) Bulk Water Average Density Bulk Water d Bulk Water  o (d) Present Even if Water UNPERTURBED from Bulk

13. What determines variations in surface water density?

14. Simple View of Protein Surface (1) Topography Protuberance Depression (2) Electric Field qiqi qjqj qkqk h=Surface Topographical Perturbation L=17 surface L=3 surface

15. Surface Topography, Electric Field and Density Variations Low  High  O H H High  High 

16. Water Dipoles Align with Protein E Field Water Density Variations Correlated with Surface Topography and Local E Field from Protein Physical Picture:

17. Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition? Structure of Protein Hydration Water Relevance to Function?

18. The Protein Glass Transition d d n n Onset of Protein Function

19. Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition? Structure of Protein Hydration Water Relevance to Function?

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

21. Free Energy Profiles of Dominant Principal Components

22. Mode Incipient at Myoglobin Glass Transition

23. Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition? Structure of Protein Hydration Water Relevance to Function?

24. Parting Thoughts Protein Hydration: Topography and Electric Field Glass Transition: Water Translation Drives Small Number of Global Motions Glass Transition and Function: ?