The effect of crystal packing on oligonucleotide double helix structure

Richard E. Dickerson, David Goodsell, Mary L. Kopka, Philip E. Pjura

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

One of the questions that constantly is asked regarding x-ray crystal structure analyses of macromolecules is: To what extent is the observed crystal structure representative of the molecular conformation when free in solution, and to what degree is the structure perturbed by intermolecular crystal forces? This can be assessed with DNA oligomers because of an unusual aspect of crystallization: Self-complementary oligomers should possess a twofold symmetry axis normal to their helix axis, yet more often than not, crystals of such oligomers do not use this internal symmetry. The two ends of the helix are crystallographically distinct though chemically identical. Complexes of DNA oligomers with intercalating drugs such as triostin A tend to use their twofold symmetry when they crystallize, whereas complexes with non-intercalating, groove-binding drugs ignore this symmetry unless the drug molecule is very small. A detailed examination of crystal packing in the dodecamer C-G-C-G-A-A-T-T-C-G-C-G provides an explanation of all of the foregoing behavior, in terms of the mechanism of nucleation of DNAor DNA-drug complexes on the surface of a growing crystal. Asymmetry of the ends of the DNA helix is the price that is paid for efficient lateral packing of helices within the crystal. The actual end-for-end variation in standard helix parameters is compared with the experimental noise level as gauged by independent re-refinement of the same oligonucleotide structure where available, and with the observed extent of variation of these same parameters along the helix. Oligomers analyzed are the B-DNA dodecamer C-G-C-G-A-A-T-T -C-G-C-G, the A-DNA octamer G-G-T-A-T -A-C-C, and the phosphorothioate analogue of the B-DNA hexamer G-C-G-C-G-C. End-for-end variation, presumably the result of crystal packing, is typically double the experimental noise level, and half the variation in the same parameter along the helix. Analysis of crystal packing in the phosphorothioate hexamer, which uses the same P212121 space group as the dodecamer, shows that the highly unsymmetrical B1 vs. B11 backbone conformation probably is to be ascribed to crystal packing forces, and not to the sequence of the hexamer.

Original languageEnglish (US)
Pages (from-to)557-579
Number of pages23
JournalJournal of Biomolecular Structure and Dynamics
Volume5
Issue number3
DOIs
StatePublished - Jan 1 1987

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Oligonucleotides
B-Form DNA
DNA
Pharmaceutical Preparations
Noise
A-Form DNA
Molecular Conformation
Crystallization
X-Rays

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

Dickerson, Richard E. ; Goodsell, David ; Kopka, Mary L. ; Pjura, Philip E. / The effect of crystal packing on oligonucleotide double helix structure. In: Journal of Biomolecular Structure and Dynamics. 1987 ; Vol. 5, No. 3. pp. 557-579.
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The effect of crystal packing on oligonucleotide double helix structure. / Dickerson, Richard E.; Goodsell, David; Kopka, Mary L.; Pjura, Philip E.

In: Journal of Biomolecular Structure and Dynamics, Vol. 5, No. 3, 01.01.1987, p. 557-579.

Research output: Contribution to journalArticle

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N2 - One of the questions that constantly is asked regarding x-ray crystal structure analyses of macromolecules is: To what extent is the observed crystal structure representative of the molecular conformation when free in solution, and to what degree is the structure perturbed by intermolecular crystal forces? This can be assessed with DNA oligomers because of an unusual aspect of crystallization: Self-complementary oligomers should possess a twofold symmetry axis normal to their helix axis, yet more often than not, crystals of such oligomers do not use this internal symmetry. The two ends of the helix are crystallographically distinct though chemically identical. Complexes of DNA oligomers with intercalating drugs such as triostin A tend to use their twofold symmetry when they crystallize, whereas complexes with non-intercalating, groove-binding drugs ignore this symmetry unless the drug molecule is very small. A detailed examination of crystal packing in the dodecamer C-G-C-G-A-A-T-T-C-G-C-G provides an explanation of all of the foregoing behavior, in terms of the mechanism of nucleation of DNAor DNA-drug complexes on the surface of a growing crystal. Asymmetry of the ends of the DNA helix is the price that is paid for efficient lateral packing of helices within the crystal. The actual end-for-end variation in standard helix parameters is compared with the experimental noise level as gauged by independent re-refinement of the same oligonucleotide structure where available, and with the observed extent of variation of these same parameters along the helix. Oligomers analyzed are the B-DNA dodecamer C-G-C-G-A-A-T-T -C-G-C-G, the A-DNA octamer G-G-T-A-T -A-C-C, and the phosphorothioate analogue of the B-DNA hexamer G-C-G-C-G-C. End-for-end variation, presumably the result of crystal packing, is typically double the experimental noise level, and half the variation in the same parameter along the helix. Analysis of crystal packing in the phosphorothioate hexamer, which uses the same P212121 space group as the dodecamer, shows that the highly unsymmetrical B1 vs. B11 backbone conformation probably is to be ascribed to crystal packing forces, and not to the sequence of the hexamer.

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