Structure and conformation of N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine. A theoretical ab initio study

Andrzej Leś, Ludwik Adamowicz, Wojciech Rode

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Optimal molecular geometries and molecular energies were obtained for N4-hydroxycytosine and its 5-fluoro congener with the use of the theoretical ab initio quantum mechanical calculations within the Self Consistent Field method corrected for the electron correlation effects by the second-order Many Body Perturbation Theory (SCF + MBPT(2)). The 6-31G Gaussian basis set was employed. Several tautomeric and rotameric forms were considered. For N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine the imino tautomer (in the conformation syn relatively to the N3-nitrogen atom) appeared to be the most stable form. The imino tautomer of N4-hydroxy-cytosine in the anti rotameric form is by 12.8 kJ mol-1 less stable than the imino-syn form. The 5-fluoro substituent raises the energy difference between the syn and anti rotamers up to 38.5 kJ mol-1. The potential energy barrier for the syn-anti rotation in the imino form of N4-hydroxycytosine is estimated to be about 180 kJ/mol. The results presented in this paper suggest that the syn-imino and anti-imino forms can be treated as two structural isomers that do not interconvert at temperatures relevant to biochemical conditions. The theoretical results also show that the amino tautomeric forms do not compete with the imino forms in the gas-phase and in non-polar and weakly-polar environment. In a polar environment (e.g., in aqueous solutions), however, one may expect an increased population of the amino forms. Qualitatively, the results of the present study agree well with the available experimental and theoretical data for N4-hydroxycytosine and some of its derivatives. The implications of the present study are discussed in relation to the molecular mechanisms of mutagenesis caused by NH2OH and of enzyme (thymidylate synthase) inhibition by N4-hydroxydeoxycytidine monophosphate.

Original languageEnglish (US)
Pages (from-to)39-48
Number of pages10
JournalBBA - Gene Structure and Expression
Volume1173
Issue number1
DOIs
StatePublished - Apr 29 1993

Fingerprint

Flucytosine
Electron correlations
Thymidylate Synthase
Mutagenesis
Cytosine
Energy barriers
Potential energy
Isomers
Conformations
Nitrogen
Gases
Derivatives
Atoms
Geometry
Enzymes
Electrons
Temperature
Population
5-hydroxycytosine

Keywords

  • Ab initio calculation
  • Base-pairing
  • Hydroxylamine mutagenesis
  • N-Hydroxycytosine
  • Nucleic acid base analog
  • Tautomerism
  • Thymidylate synthase

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Genetics
  • Structural Biology
  • Medicine(all)

Cite this

Structure and conformation of N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine. A theoretical ab initio study. / Leś, Andrzej; Adamowicz, Ludwik; Rode, Wojciech.

In: BBA - Gene Structure and Expression, Vol. 1173, No. 1, 29.04.1993, p. 39-48.

Research output: Contribution to journalArticle

@article{9480897df42f4b19889c0e82c486450a,
title = "Structure and conformation of N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine. A theoretical ab initio study",
abstract = "Optimal molecular geometries and molecular energies were obtained for N4-hydroxycytosine and its 5-fluoro congener with the use of the theoretical ab initio quantum mechanical calculations within the Self Consistent Field method corrected for the electron correlation effects by the second-order Many Body Perturbation Theory (SCF + MBPT(2)). The 6-31G Gaussian basis set was employed. Several tautomeric and rotameric forms were considered. For N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine the imino tautomer (in the conformation syn relatively to the N3-nitrogen atom) appeared to be the most stable form. The imino tautomer of N4-hydroxy-cytosine in the anti rotameric form is by 12.8 kJ mol-1 less stable than the imino-syn form. The 5-fluoro substituent raises the energy difference between the syn and anti rotamers up to 38.5 kJ mol-1. The potential energy barrier for the syn-anti rotation in the imino form of N4-hydroxycytosine is estimated to be about 180 kJ/mol. The results presented in this paper suggest that the syn-imino and anti-imino forms can be treated as two structural isomers that do not interconvert at temperatures relevant to biochemical conditions. The theoretical results also show that the amino tautomeric forms do not compete with the imino forms in the gas-phase and in non-polar and weakly-polar environment. In a polar environment (e.g., in aqueous solutions), however, one may expect an increased population of the amino forms. Qualitatively, the results of the present study agree well with the available experimental and theoretical data for N4-hydroxycytosine and some of its derivatives. The implications of the present study are discussed in relation to the molecular mechanisms of mutagenesis caused by NH2OH and of enzyme (thymidylate synthase) inhibition by N4-hydroxydeoxycytidine monophosphate.",
keywords = "Ab initio calculation, Base-pairing, Hydroxylamine mutagenesis, N-Hydroxycytosine, Nucleic acid base analog, Tautomerism, Thymidylate synthase",
author = "Andrzej Leś and Ludwik Adamowicz and Wojciech Rode",
year = "1993",
month = "4",
day = "29",
doi = "10.1016/0167-4781(93)90240-E",
language = "English (US)",
volume = "1173",
pages = "39--48",
journal = "Biochimica et Biophysica Acta - Gene Structure and Expression",
issn = "0167-4781",
publisher = "Elsevier BV",
number = "1",

}

TY - JOUR

T1 - Structure and conformation of N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine. A theoretical ab initio study

AU - Leś, Andrzej

AU - Adamowicz, Ludwik

AU - Rode, Wojciech

PY - 1993/4/29

Y1 - 1993/4/29

N2 - Optimal molecular geometries and molecular energies were obtained for N4-hydroxycytosine and its 5-fluoro congener with the use of the theoretical ab initio quantum mechanical calculations within the Self Consistent Field method corrected for the electron correlation effects by the second-order Many Body Perturbation Theory (SCF + MBPT(2)). The 6-31G Gaussian basis set was employed. Several tautomeric and rotameric forms were considered. For N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine the imino tautomer (in the conformation syn relatively to the N3-nitrogen atom) appeared to be the most stable form. The imino tautomer of N4-hydroxy-cytosine in the anti rotameric form is by 12.8 kJ mol-1 less stable than the imino-syn form. The 5-fluoro substituent raises the energy difference between the syn and anti rotamers up to 38.5 kJ mol-1. The potential energy barrier for the syn-anti rotation in the imino form of N4-hydroxycytosine is estimated to be about 180 kJ/mol. The results presented in this paper suggest that the syn-imino and anti-imino forms can be treated as two structural isomers that do not interconvert at temperatures relevant to biochemical conditions. The theoretical results also show that the amino tautomeric forms do not compete with the imino forms in the gas-phase and in non-polar and weakly-polar environment. In a polar environment (e.g., in aqueous solutions), however, one may expect an increased population of the amino forms. Qualitatively, the results of the present study agree well with the available experimental and theoretical data for N4-hydroxycytosine and some of its derivatives. The implications of the present study are discussed in relation to the molecular mechanisms of mutagenesis caused by NH2OH and of enzyme (thymidylate synthase) inhibition by N4-hydroxydeoxycytidine monophosphate.

AB - Optimal molecular geometries and molecular energies were obtained for N4-hydroxycytosine and its 5-fluoro congener with the use of the theoretical ab initio quantum mechanical calculations within the Self Consistent Field method corrected for the electron correlation effects by the second-order Many Body Perturbation Theory (SCF + MBPT(2)). The 6-31G Gaussian basis set was employed. Several tautomeric and rotameric forms were considered. For N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine the imino tautomer (in the conformation syn relatively to the N3-nitrogen atom) appeared to be the most stable form. The imino tautomer of N4-hydroxy-cytosine in the anti rotameric form is by 12.8 kJ mol-1 less stable than the imino-syn form. The 5-fluoro substituent raises the energy difference between the syn and anti rotamers up to 38.5 kJ mol-1. The potential energy barrier for the syn-anti rotation in the imino form of N4-hydroxycytosine is estimated to be about 180 kJ/mol. The results presented in this paper suggest that the syn-imino and anti-imino forms can be treated as two structural isomers that do not interconvert at temperatures relevant to biochemical conditions. The theoretical results also show that the amino tautomeric forms do not compete with the imino forms in the gas-phase and in non-polar and weakly-polar environment. In a polar environment (e.g., in aqueous solutions), however, one may expect an increased population of the amino forms. Qualitatively, the results of the present study agree well with the available experimental and theoretical data for N4-hydroxycytosine and some of its derivatives. The implications of the present study are discussed in relation to the molecular mechanisms of mutagenesis caused by NH2OH and of enzyme (thymidylate synthase) inhibition by N4-hydroxydeoxycytidine monophosphate.

KW - Ab initio calculation

KW - Base-pairing

KW - Hydroxylamine mutagenesis

KW - N-Hydroxycytosine

KW - Nucleic acid base analog

KW - Tautomerism

KW - Thymidylate synthase

UR - http://www.scopus.com/inward/record.url?scp=0027193259&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027193259&partnerID=8YFLogxK

U2 - 10.1016/0167-4781(93)90240-E

DO - 10.1016/0167-4781(93)90240-E

M3 - Article

VL - 1173

SP - 39

EP - 48

JO - Biochimica et Biophysica Acta - Gene Structure and Expression

JF - Biochimica et Biophysica Acta - Gene Structure and Expression

SN - 0167-4781

IS - 1

ER -