Dynamics of Proteins and their hydration water 

The glassy behavior of proteins has been a topic of many experimental and theoretical publications over the past decade or so, and recently there has been a resurgence of research activity concerning the subject. The topic is of immmense intrinsic interest, and has potential applications in structural biology and biotechnology. Of particular interest  have been hallmarks of glassy behavior on short time scales (1ns) and atomic length scales that may be probed by incoherent neutron scattering. The abundance of neutron data has prompted a large number of molecular dynamics simulations studies aimed at interpreting the data. However, since the first such simulations were performed about ten years ago, all calculations to date have failed to quantitatively reproduce the neutron results and simulations reporting similar failures continue to appear. The long-standing descrepancies wih experiment, reported for several proteins by several groups using  diffreent force-fields, have been blamed on the form of current generation force-fields, and this has implication for all protein dynamics calculations.

During the last couple of years since entering this field, we have focused on developping protocols for obtaining quantitative agreement with key experimental data. In addition to providing a firm basis for the interpretation of experimental data, our efforts to achieve quantitative accuracy have revealed that taking shortcuts can lead to qualitatively incorrect conclusions.
 
 

• Effects of Solvent Damping on Side Chain and Backbone Contributions to the Protein Boson Peak

Tarek M. and Tobias D.J.                J. Chem. Phys.    115, 1607-1612    (2001).

We report a MD simulation study of the behavior of the boson  peak of a globular protein in ealistic powder environments  corresponding to conditions of neutron scattering studies (hydrated at 150 K, dry at 150 K, and dry at 300 K).  The temperature and hydration dependence of the boson peak are in excellent agreement with neutron scattering data on powder samples of several proteins.  To gain further insight into the nature of boson peak, and its relation to hydration water, we have decomposed the inelastic spectrum into contributions from  the protein backbone, non-polar side chains in the interior of  the protein, and polar side chains exposed to the solvent. We find that the boson peak arises from motions distributed throughout the protein, regardless of the conditions of  temperature and hydration.  Furthermore, the relative contribution from each part of the protein considered shows a similar temperature and hydration dependence.  The boson peak appears not to be specifically  due to water-coupled motions of the polar side chains, but rather to motions propagating through the whole protein.  
 

• The Dynanmics of Protein Hydration Water: A Quantitative Comparison of MD Simulations and Neutron Scattering Experiments 

Tarek M. and Tobias D.J.                Bioph. J.  79, 3244-3257  (2000).

We present results of extensive and detailed molecular dynamics simualtions of hydrated Ribonuclease A protein, as a function of temperature and environment. The dynamics of protein hydration water appear to be very similar in crystal and powder environments at moderate to high hydration levels.  Thus, we contend that experiments performed on powder samples are appropriate for discussing hydration water dynamics in native protein environments (and vice versa). The study reveals that traditional simulation performed on clusters of proteins surrounded by a finite water shell are not appropriate for the study of the solvent dynamics. Detailed comparison to available X-ray and neutron inelastic experiments, shows that current generation force fields, reproduces accurately the structural and dynamical observables. We have analyzed the water dynamics on the time scale of tens of picoseconds. At room temperature and high hydration, significant water translational diffusion and rotational motion occur. At low hydration, the water molecules are translationally confined but display appreciable
rotational motion. Below the protein dynamical transition, i.e. at 150 K, both translational and rotational motions of the water molecules are essentially arrested.  These result, suggest that water translational motion is necessary for the structural relaxation that permits anharmonic and diffusive motions in proteins.  Furthermore, it appears that the exchange of protein-water hydrogen bonds by water rotational/librational motion, is not sufficient to permit protein structural relaxation.  Rather, that complete exchange of protein-bound water molecules by translational displacement seems to be  required.
 

• Amplitudes and Frequencies of Protein Dynamics: Analysis of Discrepancies Between Neutron Scattering and Molecular Dynamics Simulations

Tarek M. and Tobias D.J.               J. Amer. Chem. Soc.  122, 10450-10451  (2000). 

Molecular dynamics simulations have ben used extensively  in recent years in an atttemps to investigate aspects of the glassy behavior of proteins at the atomic level. Among these are the sharp increase (dynamical transition) in atomic mean-squareed displacements that occur arround 200 K, and the appearence of a "boson peak" in inelastic spectra measured by incoherent neutron scattering. Several groups using different force-fields have systematiccaly overestimated the mean-squared displacements and underestimated the frequency of the boson peak, compared to neutron data. These discrepancies have been attributed to a flaw in current generation force-fields. We report an analysis of the protein dynamics in an extensive series of MD simulations of Ribonuclease A in cluster, crystal and powder environments over a wide temperature range. As in previous studies, our cluster results are in poor agreement with neutron data. However a more realistic representation of the environment in our crystal and powder simulations leads to much better agreement. In the crystal simulations we have been able to more accurately reproduce the dynamical transition reflected by the mean-squared displacements, and greatly improve the frequency distribution in the vicinity of the boson peak. At low tempearture we obtain a broad boson peak centered at about 3 meV. The modification of the position and the shape of the peak observed experimentally are also reproduced. Our results vindicate to a large extent current generation force-fields used in protein simulations. 
 

• Environmental Dependence of the Dynamics of Protein Hydration Water

Tarek M. and Tobias D.J.              J. Amer. Chem. Soc. 121, 9740-9741 (1999) 

We report a molecular dynamics (MD) simulation study that addresses the question: does the picosecond dynamics of hydration water depend on the protein environment? We compare water mobility in a crystal, dry and hydrated powders, and a protein/water "cluster" model commonly employed in MD simulations. Our principal findings are: (1) the overall water mobility on the time scale of tens of picoseconds is essentially identical in the crystal and hydrated powders; (2) water mobility is significantly higher in a cluster compared to the crystal and powder at a given  hydration level. These results suggest that experiments performed on powder samples are appropriate for discussing water dynamics in native protein environments and that simulations of clusters do not give a quantitatively correct picture of water dynamics near protein surfaces.
 
 
 

**Current topics of research: 
The study of the role of the solvent in the glassy behavior of proteins.
Investigation of the origin of the boson peak in proteins and water. 

tarek@jazz.ncnr.nist.gov

Last modified: Sept. 5, 1999