This project focuses on the study of membranes and carbohydrates by molecular dynamics computer simulation. Modeling studies, primarily on proteins and in collaboration with experimental groups, are also carried out.? ? This years accomplishments primarily concerned force field and method development, and NMR relaxation studies.? ? Force fields (FF) on three classes of compounds, ethers, carbohydrates, and lipids, were developed. All involved extensive ab initio calculations on small model compounds, followed by extensive molecular dynamics simulations on the target systems to ensure that a variety of target data were reproduced. The first CHARMM ether FF was published (4), and follow-up work on polyethylene glycol will be submitted shortly. Following validation of methods on a model carbohydrate, 2- Ethoxy Tetrahydropyran (3), a comprehensive reparameterization of the CHARMM carbohydrate FF was carried out for monosaccharides. Excellent agreement with experimental pucker angles, and the distributions and relaxation rates of the exocyclic torsion hydroxyl group, and solution density data has been obtained. Lastly, the reparameterization of the lipid FF is nearly complete. The key turned out to be a hydrogen bond between the carbonyl group of chain 2 and the glycerol group. This previously unknown interaction leads the splitting of the deuterium order parameters for the carbon 1 of the glycerol and carbon 2 of chain two. A summary of lipid parameterization efforts is contained in (5).? ? 31C and 31P spin lattice relaxation rates were evaluated for two different sized DPPC bilayers and compared with experiment. Agreement is excellent, and demonstrated that collective motions are not playing a substantial role in NMR relaxation over the frequency range 0.022 to 21.1 T. Fits to an analytic model then demonstrated that the primary component of the slow relaxation time observer in the NMR arises from lipid wobble. These results substantially increase confidence in current FF, and lend fundamental insight into the underlying dynamics of membranes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Intramural Research (Z01)
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National Heart, Lung, and Blood Institute
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Lee, Hwankyu; de Vries, Alex H; Marrink, Siewert-Jan et al. (2009) A coarse-grained model for polyethylene oxide and polyethylene glycol: conformation and hydrodynamics. J Phys Chem B 113:13186-94
Woodcock, H Lee; Brooks, Bernard R; Pastor, Richard W (2008) Pathways and populations: stereoelectronic insights into the exocyclic torsion of 5-(hydroxymethyl)tetrahydropyran. J Am Chem Soc 130:6345-7
Klauda, Jeffery B; Eldho, Nadukkudy V; Gawrisch, Klaus et al. (2008) Collective and noncollective models of NMR relaxation in lipid vesicles and multilayers. J Phys Chem B 112:5924-9
Miller, Benjamin T; Zheng, Wenjun; Venable, Richard M et al. (2008) Langevin network model of myosin. J Phys Chem B 112:6274-81
Lee, Hwankyu; Venable, Richard M; Mackerell Jr, Alexander D et al. (2008) Molecular dynamics studies of polyethylene oxide and polyethylene glycol: hydrodynamic radius and shape anisotropy. Biophys J 95:1590-9
Klauda, Jeffery B; Roberts, Mary F; Redfield, Alfred G et al. (2008) Rotation of lipids in membranes: molecular dynamics simulation, 31P spin-lattice relaxation, and rigid-body dynamics. Biophys J 94:3074-83
Klauda, Jeffery B; Wu, Xiongwu; Pastor, Richard W et al. (2007) Long-range Lennard-Jones and electrostatic interactions in interfaces: application of the isotropic periodic sum method. J Phys Chem B 111:4393-400
Woodcock, H Lee; Moran, Damian; Pastor, Richard W et al. (2007) Ab initio modeling of glycosyl torsions and anomeric effects in a model carbohydrate: 2-ethoxy tetrahydropyran. Biophys J 93:1-10
Klauda, Jeffery B; Kucerka, Norbert; Brooks, Bernard R et al. (2006) Simulation-based methods for interpreting x-ray data from lipid bilayers. Biophys J 90:2796-807
Buck, Matthias; Bouguet-Bonnet, Sabine; Pastor, Richard W et al. (2006) Importance of the CMAP correction to the CHARMM22 protein force field: dynamics of hen lysozyme. Biophys J 90:L36-8

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