Molecular dynamics simulations of B‐DNA: An analysis of the role of initial molecular configuration, randomly assigned velocity distribution, long integration times, and nonconstrained termini

Abstract

Molecular dynamics simulations of three DNA sequences using the AMBER 3.0 force field were performed with implicit inclusion of water through a distance-dependent dielectric constant and solvated counterions. Simulations of the self-complementary DNA dodecamer d(CGCGAATTCGCG) were started from a regular B-DNA structure and the x-ray single crystal B-DNA structure. Although mean convergence during the 89-ps calculation was confirmed, localized differences in backbone torsionals and base-pair helicoidals were observed. A nanosecond simulation of the nonself-complementary 14 base-pair DNA d(GGCGGAATTGGCGG) indicates that most structural parameters stabilize within the first 100-200 ps, while isolated features show low-frequency oscillations throughout the calculation. The lack of harmonic constraints on the ends of the molecules was shown not to perturb the structural dynamics of the internal oligonucleotide beyond the external 2 base pairs. Comparison of three simulations of the nonself-complementary 14 base-pair DNA d(GGCGAAATTCGCGG), identical in all respects other than the assignment of initial Maxwellian atomic velocity distributions, revealed the inherent systematic variability. The three calculations result in nearly superimposable global structures, with localized variations in torsionals and helicoidals. Our results provide a basis for performing a comparative analysis of the effect of DNA sequence on localized structure.

Molecular Modeling of the Intrastrand Guanine-Guanine DNA Adducts Produced by Cisplatin and Oxaliplatin

“…Although the structures displayed minimal divergence, there was a narrowing of the major groove in the oxaliplatin final structure relative to the cisplatin final structure. Following a method previously described (Falsafi and Reich, 1993), the major groove width was measured as the distance between the phosphate group of one nucleotide and the phosphate group of its closest neighbor across the groove (this nucleotide was five to six steps down the helix from the first in our molecules). Measured in this way, the average major groove width was 14.2 Ϯ 2.3 Å in the cisplatin molecule but only 12.2 Ϯ 0.8 Å in the oxaliplatin molecule (similar to the crystal structure width of 11.7 Ϯ 1.4 Å) The narrowed major groove suggests the possibility of a more A-DNA-like conformation in the case of oxaliplatin.…”

“…However, the extremely high central processing unit demands and run times of these methods precluded their use in this study, and the reader is therefore cautioned to take note of this limitation. Implicit solvent techniques have been suggested to provide acceptable accu-racy for DNA modeling (Falsafi and Reich, 1993;Kozack and Loechler, 1997), and this initial work provides a foundation for the eventual exploration of strained, platinated DNA molecules with the advanced full solvent techniques mentioned above.…”

A 5-nanosecond molecular dynamics trajectory for B-DNA: analysis of structure, motions, and solvation

“…The oligonucleotide duplex of sequence d(CGCGAAT-TCGCG)2 was the first to crystallize in the B-form of DNA (Dickerson and Drew, 1981;Wing et al, 1980). The structure of this sequence has been the subject of a considerable number of subsequent crystallographic (Dickerson et al, 1985;Holbrook et al, 1985;Kopka et al, 1985;Nunn et al, 1993;Teng et al, 1988;Westhof, 1987), NMR (Alam et al, 1991;Hare et al, 1983;Lane et al, 1991;Liepinsh et al, 1992;Russu, 1990, 1992;Nerdal et al, 1989; Ott and Eckstein, 1985;Patel et al, 1982;Pelton and Wemmer, 1988;Withka et al, 1992) and Raman spectroscopic investigations (Wang et al, 1987;Weidlich et al, 1990), and now serves the field as a benchmark system for further experimental and theoretical (Beveridge et al, 1990; Falsafi and Reich, 1993;McConnell et al, 1994;Miaskiewicz et al, 1993;Prevost et al, 1993; Rao and Kollman, 1990; Ravishanker et al, 1989;Srinivasan et al, 1990;Subramanian and Beveridge, 1989;Subramanian et al, 1988Subramanian et al, , 1990Swaminathan et al, 1991;Withka et al, 1992) studies. The central 6 bp of this sequence are the recognition site for the EcoRI restriction endonuclease, characterized at the molecular level in the first protein-DNA crystal structure (Frederick et al, 1984).…”

Macroscopic localization lengths of vibrational normal modes in a heuristic DNA model

“…The study of the molecular dynamics of DNA has gained increasing attention, some studies have developed detailed models 18 for the representation of exact classical solutions. Unfortunately, the computational cost is so high that only has been simulated DNA fragments, 19 which is far from characterize physical and biological processes such as replication, transcription, and denaturation.…”