Theoretical Studies of the Dynamics of Proteins and their Hydration Water

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Tobias MCB 0078278The objective of this project is to study the dynamics of native and partially unfolded proteins and their solvent on time scales ranging from femtoseconds to nanoseconds, using molecular dynamics (MD) simulations. The role of solvent dynamics in affecting the protein structural relaxation accompanying the dynamical "glass" transition will be investigated using molecular MD simulations of ribonuclease A in crystals, dry and hydrated powders, and a glycerol/water solution, at temperatures above and below the transition. MD simulations, in conjunction with neutron scattering experiments, will be used to characterize the picosecond dynamics of the molten globule state of alpha-lactalbumin. The dynamics of surface associated water in simulations of the native and molten globule states of alpha-lactalbumin will be compared in an attempt to reconcile the traditional view of an expanded, solvent penetrated molten globule with recently reported magnetic relaxation dispersion data that challenged this picture. Finally, vibrational energy storage and relaxation in heme proteins will be investigated. A series of MD simulations will be carried out to investigate heme cooling and dissipation of vibrational energy by the protein matrix and solvent in a myoglobin solution at room temperature, the storage of energy in boson peak vibrations following heme excitation in low hydration, low temperature glassy states of myoglobin, and CO dissociation in a myoglobin crystal to address questions concerning environmental effects in time-resolved crystallographic studies. Techniques of non-stationary time series analysis will be employed to generate joint time-frequency distributions for visualizing the flow of vibrational energy between modes at equilibrium and vibrational energy relaxation following a perturbation.A complete understanding of the folding and function of proteins requires knowledge of the structures, energetics, and dynamics of native and denatured proteins. This project will provide an accurate picture of the changes in protein dynamics on making the transition from an inactive, glassy state at low temperature, to an active state at higher temperatures, as well as further insight into the role of the solvent in affecting this transition. In addition, the work on heme proteins will contribute to the understanding of fundamental chemical dynamical processes connected to protein function, and will produce new tools for the analysis of simulations of complex protein dynamics. It is anticipated that this research should prove useful in the interpretation of experimental measurements on protein dynamics, as a close correspondence with spectroscopic experiments is emphasized in the design of the simulations and the analysis of the results.