Showing papers by "Thomas E. Cheatham published in 1999"

A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat.

Abstract: We have examined some subtle parameter modifications to the Cornell et al. force field, which has proven quite successful in reproducing nucleic acid properties, but whose C2'-endo sugar pucker phase and helical repeat for B DNA appear to be somewhat underestimated. Encouragingly, the addition of a single V2 term involving the atoms C(sp3)-O-(sp3)-C(sp3)-N(sp2), which can be nicely rationalized because of the anomeric effect (lone pairs on oxygen are preferentially oriented relative to the electron withdrawing N), brings the sugar pucker phase of C2'-endo sugars to near perfect agreement with ab initio calculations (W near 162 degrees). Secondly, the use of high level ab initio calculations on entire nucleosides (in contrast to smaller model systems necessitated in 1994-95 by computer limitations) lets one improve the chi torsional potential for nucleic acids. Finally, the O(sp3)-C(sp3)- C(sp3)-O(sp3) V2 torsional potential has been empirically adjusted to reproduce the ab initio calculated relative energy of C2'-endo and C3'-endo nucleosides. These modifications are tested in molecular dynamics simulations of mononucleosides (to assess sugar pucker percentages) and double helices of DNA and RNA (to assess helical and sequence specific structural properties). In both areas, the modified force field leads to improved agreement with experimental data.

Restrained molecular dynamics of solvated duplex DNA using the particle mesh Ewald method

Abstract: Restrained and unrestrained aqueous solution molecular dynamics simulations applying the particle mesh Ewald (PME) method to DNA duplex structures previously determined via in vacuo restrained molecular dynamics with NMR-derived restraints are reported. Without experimental restraints, the DNA decamer, d(CATTTGCATC)⋅d(GATGCAAATG) and trisdecamer, d(AGCTTGCCTTGAG)⋅d(CTCAAGGCAAGCT), structures are stable on the nanosecond time scale and adopt conformations in the B-DNA family. These free DNA simulations exhibit behavior characteristic of PME simulations previously performed on DNA sequences, including a low helical twist, frequent sugar pucker transitions, BI- BII(e−ζ) transitions and coupled crankshaft (α−γ) motion. Refinement protocols similar to the original in vacuo restrained molecular dynamics (RMD) refinements but in aqueous solution using the Cornell et al. force field [Cornell et al. (1995) J. Am. Chem. Soc., 117, 5179–5197] and a particle mesh Ewald treatment produce structures which fit the restraints very well and are very similar to the original in vacuo NMR structure, except for a significant difference in the average helical twist. Figures of merit for the average structure found in the RMD PME decamer simulations in solution are equivalent to the original in vacuo NMR structure while the figures of merit for the free MD simulations are significantly higher. The free MD simulations with the PME method, however, lead to some sequence-dependent structural features in common with the NMR structures, unlike free MD calculations with earlier force fields and protocols. There is some suggestion that the improved handling of electrostatics by PME improves long-range structural aspects which are not well defined by the short-range nature of NMR restraints.