High propeller twist and unusual hydrogen bonding patterns from the MD simulation of (dG)6.(dC)6.

A molecular dynamics (MD) study of (dG)6.(dC)6 including counter ions and 292 water molecules was made. The hydrogen bonding pattern and propeller twist angles for the mini-helix are reported as averages for times spanning 21-30, 31-40, 41-50, and 51-60 ps. The propeller twist angles range from 18 degrees to 38 degrees. Bifurcated and interstrand neighboring base (twisted) hydrogen bonding patterns were found.

A molecular dynamics simulation of the (dG)6 . (dC)6 minihelix including counterions and water.

The results of a 60 ps molecular dynamics (MD) simulation of (dG)6.(dC)6 including 10 Na+ counterions and 292 water molecules are presented. All backbone angles and helix parameters for the hexamer are reported in this paper along with trajectory plots of selected angles. Hydrogen bonding between the bases along the helical axis was observed to fluctuate with time, showing the dynamic nature of the base-pairing interaction. These fluctuations gave rise to unusual hydrogen-bonding patterns. Good intrastrand base stacking and no interstrand base stacking were also observed. The hexamer minihelix retains an essentially B-DNA conformation throughout the entire simulation even though some helix parameters and backbone angles do not have strict B-DNA values. The most striking feature obtained from the simulation was a high propeller twist, which resulted in a narrow minor groove for the minihelix. It is proposed that (dG)n.(dC)n sequences are resistant to DNAase I because of this narrow minor groove in dilute aqueous solution.

Computer graphics presentations and analysis of hydrogen bonds from molecular dynamics simulation.

To obtain better insights into the dynamic nature of hydrogen bonding, computer graphics representations were introduced as an aid for the analysis of molecular dynamics trajectories. A schematic representation of hydrogen bonding patterns is generated to reflect the frequency and the type of hydrogen bonding occurring during the simulation period. Various trajectory plots for monitoring geometrical parameters and for analyzing three-center hydrogen bonding were also generated. The methods proposed are applicable to a variety of biopolymers. In this study, hydrogen bonding in the d(G)6.d(C)6 system was examined. For the nucleic acid fragments examined, three-center hydrogen bonds can be classified as in-plane and major or minor groove types. The in-plane three-center hydrogen bond represents a stable state in which both bonds simultaneously satisfy the relaxed hydrogen bonding criteria for a measurable period. On the other hand, groove three-center hydrogen bonds behave as a transient intermediate state in a flip-flop hydrogen bonding system.

A molecular dynamics study of the effect of G.T mispairs on the conformation of DNA in solution.

The effect of G.T mispair incorporation into a double-helical environment was examined by molecular dynamics simulation. The 60-ps simulations performed on the two hexanucleotide duplexes d (G3C3)2 and d(G3TC2)2 included 10 Na+ counterions and first hydration shell waters. The resulting backbone torsional angle trajectories were analyzed to select time spans representative of conformational domains. The average backbone angles and helical parameters of the last time span for both duplexes are reported. During the simulation the hexamers retained B-type DNA structures that differed from typical A- or B-DNA forms. The overall helical structures for the two duplexes are vary similar. The presence of G.T mispairs did not alter the overall helical structure of the oligonucleotide duplex. Large propeller twist and buckle angles were obtained for both duplexes. The purine/pyrimidine crossover step showed a large decrease in propeller twist in the normal duplex but not in the mismatch duplex. Upon the formation of wobble mispairs in the mismatched duplex, the guanines moved into the minor groove and the thymines moved into the major groove. This helped prevent purine/purine clash and created a deformation in the relative orientation of the glycosidic bonds. It also exposed the free O4 of the thymines in the major groove and N2 of the guanines in the minor groove to interactions with solvent and counterions. These factors seemed to contribute to the apparently higher rigidity of the mismatched duplex during the simulation.

Fluorinated nucleic acid constituents: a carbon-13 nuclear magnetic resonance study of adenosine, cytidine, uridine, and their fluorinated analogues.

Adenosine, cytidine, uridine, and their fluorinated analogues 2-fluoroadenosine, 5-fluorocytidine, and 5-fluorouridine have been analyzed by carbon-13 nuclear magnetic resonance (NMR) spectroscopy. All carbon resonances of the sugar and base moieties are assigned. The carbon-fluorine coupling constants of the base and the carbon-proton coupling constants between carbons of the base and protons of the base and the anomeric proton of the sugar have been assigned. Effects of the fluorine atom on carbon chemical shifts of the nucleoside are expressed as delta delta F values [delta delta F = delta (fluorinated nucleoside) - delta (normal nucleoside)]. Theoretical charge density calculations (CNDO/2) of the fluorinated and non-fluorinated base carbons are compared [delta ET = E (fluorinated nucleoside) - E (normal nucleoside)]. The delta delta F and delta ET values are shown to correlate very well, except where a nitrogen atom is situated beta to the fluorine atom. This apparent deviation is attributed to a lone-pair electron (LPE) effect of the nitrogen. Contributions of the LPE effect appear to vary 1JC,H and 1JC,F values in a predictable way. Long-range (four- and five-bond) carbon-fluorine coupling constants are obbserved in the base moiety. At these experimental conditions, indroduction of the fluorine atom has no measurable conformational effect on the sugar-base torsion angle.

Computer modeling of the neurotoxin binding site of acetylcholine receptor spanning residues 185 through 196.

A model of the complex between the acetylcholine receptor and the snake neurotoxin, cobratoxin, was built by molecular model building and energy optimization techniques. The experimentally identified functionally important residues of cobratoxin and the dodecapeptide corresponding to the residues 185-196 of acetylcholine receptor alpha subunit were used to build the model. Both cis and trans conformers of cyclic L-cystine portion of the dodecapeptide were examined. Binding residues independently identified on cobratoxin are shown to interact with the dodecapeptide AChR model.