Solution structure of two mismatches A · A and T · T in the K-ras gene context by nuclear magnetic resonance and molecular dynamics

V. Gervais, J. A H Cognet, M. Le Bret, Lawrence Sowers, G. V. Fazakerley

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

To mismatches, one homopurine (A · A) and the other homopyrimidine (T · T), have been incorporated at the central position N of 5'd(GCCACNAGCTC) · d(GAGCTNGTGGC) in order to study nuclear magnetic resonance spectra and molecular dynamics. These duplexes constitute the sequence 29-39 of the K-ras gene coding for Gly12, a hot spot for mutation. The NMR spectra show that the duplexes are not greatly distorted by the introduction of the mismatches and their global conformation is that of a canonical B-form double helix. For both systems, no structural change is observed in the pH range 4.7-9. For the duplex containing the homopurine A · A mismatch, we propose a type of pairing involving one hydrogen bond between the amino group of one central adenine and the nitrogen N1 of the opposite adenine. For the duplex containing the mispaired T · T bases, NMR spectra recorded in H2O at 282 K indicate that these central bases are engaged in wobble pairing, involving two imino-carbonyl hydrogen bonds. For both systems two conformations with the same donor and acceptor pattern can coexist, one being obtained from the other by a 180° rotation about the pseudodyadic axis. Exchange between the two forms is observed by NMR at low temperature for the T · T mispair and also inferred from NMR measurements on the A · A system. The presence of this exchange and its pathway has been investigated by molecular dynamics calculations on both systems. Distance restrained and unrestrained molecular dynamics are in very good agreement with the NMR data. The average structure for either mispair shows only small conformational change from normal B DNA. For each, a systematic pathway is observed for exchange between the two conformations.

Original languageEnglish (US)
Pages (from-to)279-290
Number of pages12
JournalEuropean Journal of Biochemistry
Volume228
Issue number2
DOIs
StatePublished - 1995
Externally publishedYes

Fingerprint

ras Genes
Molecular Dynamics Simulation
Molecular dynamics
Magnetic Resonance Spectroscopy
Genes
Nuclear magnetic resonance
Adenine
Hydrogen
Conformations
Hydrogen bonds
Nitrogen
Mutation
Temperature
DNA

Keywords

  • DNA structure
  • K-ras gene
  • mismatches
  • molecular dynamics
  • NMR

ASJC Scopus subject areas

  • Biochemistry

Cite this

Solution structure of two mismatches A · A and T · T in the K-ras gene context by nuclear magnetic resonance and molecular dynamics. / Gervais, V.; Cognet, J. A H; Le Bret, M.; Sowers, Lawrence; Fazakerley, G. V.

In: European Journal of Biochemistry, Vol. 228, No. 2, 1995, p. 279-290.

Research output: Contribution to journalArticle

@article{f79c12a8380341c293cc1d62a81d1250,
title = "Solution structure of two mismatches A · A and T · T in the K-ras gene context by nuclear magnetic resonance and molecular dynamics",
abstract = "To mismatches, one homopurine (A · A) and the other homopyrimidine (T · T), have been incorporated at the central position N of 5'd(GCCACNAGCTC) · d(GAGCTNGTGGC) in order to study nuclear magnetic resonance spectra and molecular dynamics. These duplexes constitute the sequence 29-39 of the K-ras gene coding for Gly12, a hot spot for mutation. The NMR spectra show that the duplexes are not greatly distorted by the introduction of the mismatches and their global conformation is that of a canonical B-form double helix. For both systems, no structural change is observed in the pH range 4.7-9. For the duplex containing the homopurine A · A mismatch, we propose a type of pairing involving one hydrogen bond between the amino group of one central adenine and the nitrogen N1 of the opposite adenine. For the duplex containing the mispaired T · T bases, NMR spectra recorded in H2O at 282 K indicate that these central bases are engaged in wobble pairing, involving two imino-carbonyl hydrogen bonds. For both systems two conformations with the same donor and acceptor pattern can coexist, one being obtained from the other by a 180° rotation about the pseudodyadic axis. Exchange between the two forms is observed by NMR at low temperature for the T · T mispair and also inferred from NMR measurements on the A · A system. The presence of this exchange and its pathway has been investigated by molecular dynamics calculations on both systems. Distance restrained and unrestrained molecular dynamics are in very good agreement with the NMR data. The average structure for either mispair shows only small conformational change from normal B DNA. For each, a systematic pathway is observed for exchange between the two conformations.",
keywords = "DNA structure, K-ras gene, mismatches, molecular dynamics, NMR",
author = "V. Gervais and Cognet, {J. A H} and {Le Bret}, M. and Lawrence Sowers and Fazakerley, {G. V.}",
year = "1995",
doi = "10.1111/j.1432-1033.1995.00279.x",
language = "English (US)",
volume = "228",
pages = "279--290",
journal = "FEBS Journal",
issn = "1742-464X",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Solution structure of two mismatches A · A and T · T in the K-ras gene context by nuclear magnetic resonance and molecular dynamics

AU - Gervais, V.

AU - Cognet, J. A H

AU - Le Bret, M.

AU - Sowers, Lawrence

AU - Fazakerley, G. V.

PY - 1995

Y1 - 1995

N2 - To mismatches, one homopurine (A · A) and the other homopyrimidine (T · T), have been incorporated at the central position N of 5'd(GCCACNAGCTC) · d(GAGCTNGTGGC) in order to study nuclear magnetic resonance spectra and molecular dynamics. These duplexes constitute the sequence 29-39 of the K-ras gene coding for Gly12, a hot spot for mutation. The NMR spectra show that the duplexes are not greatly distorted by the introduction of the mismatches and their global conformation is that of a canonical B-form double helix. For both systems, no structural change is observed in the pH range 4.7-9. For the duplex containing the homopurine A · A mismatch, we propose a type of pairing involving one hydrogen bond between the amino group of one central adenine and the nitrogen N1 of the opposite adenine. For the duplex containing the mispaired T · T bases, NMR spectra recorded in H2O at 282 K indicate that these central bases are engaged in wobble pairing, involving two imino-carbonyl hydrogen bonds. For both systems two conformations with the same donor and acceptor pattern can coexist, one being obtained from the other by a 180° rotation about the pseudodyadic axis. Exchange between the two forms is observed by NMR at low temperature for the T · T mispair and also inferred from NMR measurements on the A · A system. The presence of this exchange and its pathway has been investigated by molecular dynamics calculations on both systems. Distance restrained and unrestrained molecular dynamics are in very good agreement with the NMR data. The average structure for either mispair shows only small conformational change from normal B DNA. For each, a systematic pathway is observed for exchange between the two conformations.

AB - To mismatches, one homopurine (A · A) and the other homopyrimidine (T · T), have been incorporated at the central position N of 5'd(GCCACNAGCTC) · d(GAGCTNGTGGC) in order to study nuclear magnetic resonance spectra and molecular dynamics. These duplexes constitute the sequence 29-39 of the K-ras gene coding for Gly12, a hot spot for mutation. The NMR spectra show that the duplexes are not greatly distorted by the introduction of the mismatches and their global conformation is that of a canonical B-form double helix. For both systems, no structural change is observed in the pH range 4.7-9. For the duplex containing the homopurine A · A mismatch, we propose a type of pairing involving one hydrogen bond between the amino group of one central adenine and the nitrogen N1 of the opposite adenine. For the duplex containing the mispaired T · T bases, NMR spectra recorded in H2O at 282 K indicate that these central bases are engaged in wobble pairing, involving two imino-carbonyl hydrogen bonds. For both systems two conformations with the same donor and acceptor pattern can coexist, one being obtained from the other by a 180° rotation about the pseudodyadic axis. Exchange between the two forms is observed by NMR at low temperature for the T · T mispair and also inferred from NMR measurements on the A · A system. The presence of this exchange and its pathway has been investigated by molecular dynamics calculations on both systems. Distance restrained and unrestrained molecular dynamics are in very good agreement with the NMR data. The average structure for either mispair shows only small conformational change from normal B DNA. For each, a systematic pathway is observed for exchange between the two conformations.

KW - DNA structure

KW - K-ras gene

KW - mismatches

KW - molecular dynamics

KW - NMR

UR - http://www.scopus.com/inward/record.url?scp=0028933904&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028933904&partnerID=8YFLogxK

U2 - 10.1111/j.1432-1033.1995.00279.x

DO - 10.1111/j.1432-1033.1995.00279.x

M3 - Article

VL - 228

SP - 279

EP - 290

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

IS - 2

ER -