FY2010 - Oak Ridge National Laboratory

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Director’s R&D Fund— Neutron Sciences dispersion when dysprosium layers are coupled by an RKKY interaction through the yttrium spacer. This work was published in Journal of Physics: Condensed Matter. Inelastic neutron-scattering measurements on the Dy/Y multilayer samples prepared by Mankey are expected to begin this fall. Information Shared Haraldsen, J. T., and R. S. Fishman. 2010. “Control of Chirality Normal to the Interface of Magnetic and Non-Magnetic Hexagonal Layers.” Phys. Rev. B, Rapid Communications 81, 020404. Haraldsen J. T., and R. S. Fishman. 2010. “Spin-Wave Dynamics of Magnetic Heterostructures: Applications to Dy/Y Multilayers.” J. Phys.: Condensed Matter 22, 186002. 05140 Mapping the Protein Structure-Function-Dynamics Landscape Pratul K. Agarwal Project Description This project will dramatically impact and extend the use of neutron scattering techniques in the structurefunction-dynamics analysis of biological materials by developing experimental, analytical, and computational techniques that exploit residue-specific H/D-labeling techniques to systematically target, highlight, and distinguish the dynamics of individual H-labeled residues in otherwise functional deuterated protein systems. We will develop and apply these capabilities in model systems and demonstrate their combination and use in neutron spectroscopy, neutron crystallography, and molecular dynamics (MD) simulation. As a test system, we will use a small 53-residue protein rubredoxin from Pyrococcus furiosus (RdPf), the most thermostable protein characterized to date. Specifically, we will (1) develop protocols for expression and production of site-specific H/D-labeled RdPf, (2) explore the residue-specific temperature dependence of protein dynamics using neutron spectroscopy, (3) determine neutron crystallographic structures at identical temperatures to locate and model H-labeled residues, and (4) analyze this information with respect to high-performance MD simulations. Once developed, we will apply these techniques to analyze the specific structure-function-dynamics of the medically important enzyme dihydrofolate reductase (DHFR), which is a major target for drug design. Mission Relevance This project will dramatically impact and extend the use of neutron scattering techniques in the structurefunction-dynamics analysis of biological materials by developing experimental, analytical, and computational techniques that exploit residue-specific H/D-labeling techniques to systematically target, highlight, and distinguish the dynamics of individual H-labeled residues in otherwise functional deuterated protein systems. This program will deliver new scientific capabilities and results of particular interest to the <strong>National</strong> Institutes of Health (NIH), the <strong>National</strong> Science Foundation (NSF), and DOE programs in biomedicine, bioengineering, and biotechnology, specifically for biomedical, pharmaceutical, and bio-inspired design, and will greatly extend SNS/HFIR capabilities and the user base in the biosciences. 46
Director’s R&D Fund— Neutron Sciences Results and Accomplishments This project has investigated the interconnection between protein structure, dynamics, and function using a multidisciplinary approach on two protein targets. As a first target, the protein rubredoxin from Pyrococcus furiosus (RdPf) was radio-labeled and studied under different solvents (H 2 O and D 2 O), using neutron scattering and computational modeling. In particular, the following neutron studies were performed: (1) specific labeling of Rubredoxin methyl groups with hydrogen remainder deuterated (we measured [on Basis] this sample and a fully deuterated sample) and (2) measured protonated Rubredoxin, hydrated at 0.2 and 0.37 with D 2 O (we measured deuterated Rubredoxin hydrated with H 2 O at the same hydration levels). The goal of the experiment was to resolve a long-standing debate in the community of the role of solvent in triggering or enabling the local dynamics of a protein. Clearly at low Q, it is apparent that the water dynamics initiates at a lower T then the protein. The combination of MD simulations and neutron scattering techniques has allowed probing the local dynamics on length and time scales of 3 to 20 Å and 10 ps to 2 ns, respectively. These studies were designed to probe the coupling between surface and near-surface hydration water to the local dynamics of the protein over a temperature range from 100 K to 360 K. Computational simulations and experimental data show quantitative agreement over the entire region studied, providing a detailed picture of the thermal evolution of rubredoxin motions. The most important observation of this study has been that the onset of anharmonicity in the protein motions corresponds to the onset of function-promoting properties of the thermophilic rubredoxin. Computational modeling of thermophilic and mesophilic Rubredoxin also allowed interpretation of the neutron data. Joint computational-experimental strategy was also used to investigate the enzyme DHFR as a second target, particularly for the impact of suppression of dynamics on enzyme mechanism. The role of the solvent in driving the enzyme motions and therefore the enzyme activity has been analyzed by characterizing DHFR catalysis in an aqueous mixture of organic solvents (such as isopropanol). Our studies show that the presence of organic solvents in the medium suppresses the dynamical motions of DHFR (the structure showed little change up until 25% v/v mixture of isopropanol). Follow-on studies are planned to characterize the suppression in motions as an explanation for the decrease in enzyme activity. Information Shared Ramanathan, A., P. K. Agarwal, M. Kurnikova, and C. J. Langmead. 2010. “An Online Approach for Mining Collective Behaviors from Molecular Dynamics Simulations.” J. Comput. Biol. 17(3), 309– 324. Kamath, G., E. E. Howell, and P. K. Agarwal. 2010. “The Tail Wagging the Dog: Insights into Catalysis in R67 Dihydrofolate Reductase.” Biochemistry 49(42), 9078–9088. 47
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NEUTRON SCIENCES ..................
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FY2010 - Oak Ridge National Laboratory

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