Elizabeth Hatcher

PNA versus DNA : Effects of Structural Fluctuations on Electronic Structure and Hole-Transport Mechanisms

The effects of structural fluctuations on charge transfer in double-stranded DNA and peptide nucleic acid (PNA) are investigated. A palindromic sequence with two guanine bases that play the roles of hole donor and acceptor, separated by a bridge of two adenine bases, was analyzed using combined molecular dynamics (MD) and quantum-chemical methods. Surprisingly, electronic structure calculations on individual MD snapshots show significant frontier orbital electronic population on the bridge in approximately 10% of the structures. Electron-density delocalization to the bridge is found to be gated by fluctuations of the covalent conjugated bond structure of the aromatic rings of the nucleic bases. It is concluded, therefore, that both thermal hopping and superexchange should contribute significantly to charge transfer even in short DNA/PNA fragments. PNA is found to be more flexible than DNA, and this flexibility is predicted to produce larger rates of charge transfer.

Quantum and dynamical effects of proton donor-acceptor vibrational motion in nonadiabatic proton-coupled electron transfer reactions

This paper presents a general theoretical formulation for proton-coupled electron transfer (PCET) reactions. The solute is represented by a multistate valence bond model, and the active electrons and transferring proton(s) are treated quantum mechanically. This formulation enables the classical or quantum mechanical treatment of the proton donor-acceptor vibrational mode, as well as the dynamical treatment of the proton donor-acceptor mode and the solvent. Nonadiabatic rate expressions are presented for PCET reactions in a number of well-defined limits for both dielectric continuum and molecular representations of the environment. The dynamical rate expressions account for correlations between the fluctuations of the proton donor-acceptor distance and the nonadiabatic PCET coupling. The quantities in the rate expressions can be calculated with a dielectric continuum model or a molecular dynamics simulation of the full system. The significance of the quantum and dynamical effects of the proton donor-acceptor mode is illustrated with applications to model PCET systems.

CHARMM Additive All-Atom Force Field for Aldopentofuranoses, Methyl-aldopentofuranosides, and Fructofuranose

An additive all-atom empirical force field for aldopentofuranoses, methyl-aldopentofuranosides (Me-aldopentofuranosides), and fructofuranose carbohydrates, compatible with existing CHARMM carbohydrate parameters, is presented. Building on existing parameters transferred from cyclic ethers and hexopyranoses, parameters were further developed using target data for complete furanose carbohydrates as well as O-methyl tetrahydrofuran. The bond and angle equilibrium parameters were adjusted to reproduce target geometries from a survey of furanose crystal structures, and dihedral parameters were fit to over 1700 quantum mechanical (QM) MP2/cc-pVTZ//MP2/6-31G(d) conformational energies. The conformational energies were for a variety of complete furanose monosaccharides and included two-dimensional ring pucker energy surfaces. Bonded parameter optimization led to the correct description of the ring pucker for a large set of furanose compounds, while furanose-water interaction energies and distances reproduced QM HF/6-31G(d) results for a number of furanose monosaccharides, thereby validating the nonbonded parameters. Crystal lattice unit cell parameters and volumes, aqueous-phase densities, and aqueous NMR ring pucker and exocyclic data were used to validate the parameters in condensed-phase environments. Conformational sampling analysis of the ring pucker and exocyclic group showed excellent agreement with experimental NMR data, demonstrating that the conformational energetics in aqueous solution are accurately described by the optimized force field. Overall, the parameters reproduce available experimental data well and are anticipated to be of utility in future computational studies of carbohydrates, including in the context of proteins, nucleic acids, and/or lipids when combined with existing CHARMM biomolecular force fields.

Comparing simulated and experimental translation and rotation constants: range of validity for viscosity scaling.

Proper simulation of dynamic properties, including molecular diffusion, is an important goal of empirical force fields. However, the widely used TIP3P water model does not reproduce the experimental viscosity of water. Consequently, scaling of simulated diffusion constants of solutes in aqueous solutions is required to effectively compare them with experiment. It is proposed that scaling by the ratio of viscosities of model and real water is appropriate in the regime where the concentration dependence of simulated and experimental solution viscosities is parallel. With this ansatz, viscosity scaling can be carried out for glucose and trehalose up to 20 wt % for simulations carried out with the CHARMM additive carbohydrate force field C35 and TIP3P water; above this value, the concentration dependence of simulated viscosities lags that of experiment, and scaling is not advised. Scaled translational diffusion constants for glucose and the disaccharides trehalose, maltose, and melibiose at low concentration agree nearly quantitatively with experiment, as do NMR (13)C T(1)s for glucose, trehalose, and maltose; these results support the use of C35 for simulations of sugar transport properties at low concentration. At high concentrations the scaled diffusion constants for glucose and trehalose underestimate and overestimate experiment, respectively. Hydrodynamic bead model calculations indicate a hydration level of approximately 1 water/hydroxyl for glucose. Patterns for the disaccharides are more complicated, though trehalose binds 0.5 to 1 more water than does maltose depending on the analysis.

Solution structure of a peptide nucleic acid duplex from NMR data: features and limitations.

This paper describes the results of a 1D and 2D NMR spectroscopy study of a palindromic 8-base pair PNA duplex GGCATGCC in H2O and H2O-D2O solutions. The (1)H NMR peaks have been assigned for most of the protons of the six central base pairs, as well as for several amide protons of the backbone. The resulting 36 interbase and base-backbone distance restraints were used together with Watson-Crick restraints to generate the PNA duplex structure in the course of 10 independent simulated annealing runs followed by restrained molecular dynamics (MD) simulations in explicit water. The resulting PNA structures correspond to a P-type helix with helical parameters close to those observed in the crystal structures of PNA. Based on the current limited number of restraints obtained from NMR spectra, alternative structures obtained by MD from starting PNA models based on DNA cannot be ruled out and are also discussed.

Bifurcated hydrogen bonding and asymmetric fluctuations in a carbohydrate crystal studied via X-ray crystallography and computational analysis.

The structure of the O-methyl glycoside of the naturally occurring 6-O-[(R)-1-carboxyethyl]-α-D-galactopyranose, C10H18O8, has been determined by X-ray crystallography at 100 K, supplementing the previously determined structure obtained at 293 K (Acta Crystallogr.1996, C52, 2285-2287). Molecular dynamics simulations of this glycoside were performed in the crystal environment with different numbers of units cells included in the primary simulation system at both 100 and 293 K. The calculated unit cell parameters and the intramolecular geometries (bonds, angles, and dihedrals) agree well with experimental results. Atomic fluctuations, including B-factors and anisotropies, are in good agreement with respect to the relative values on an atom-by-atom basis. In addition, the fluctuations increase with increasing simulation system size, with the simulated values converging to values lower than those observed experimentally indicating that the simulation model is not accounting for all possible contributions to the experimentally observed B-factors, which may be related to either the simulation time scale or size. In the simulations, the hydroxyl group of O7 is found to form bifurcated hydrogen bonds with O6 and O8 of an adjacent molecule, with the interactions dominated by the HO7-O6 interaction. Quantum mechanical calculations support this observation.