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Insights into the DNA repair process by the formamidopyrimidine-DNA glycosylase investigated by molecular dynamics

¹ Laboratoire de Dynamique Moléculaire and
² Laboratoire des Protéines Membranaires, Institut de Biologie Structurale Jean-Pierre Ebel Commissariat à l’énergie Atomique (CEA)/Centre National de la Recherche Scientifique (CNRS)/Université Joseph Fourier (UJF), 38027 Grenoble Cedex 1, France
³ Centre de Biophysique Moléculaire Unité Propre de Recherche 4301, Centre National de la Recherche Scientifique (CNRS), 45071 Orléans Cedex 02, France.

(RECEIVED March 29, 2004; FINAL REVISION May 18, 2004; ACCEPTED May 18, 2004)

Formamidopyrimidine-DNA glycosylase (Fpg) identifies and removes 8-oxoguanine from DNA. All of the X-ray structures of Fpg complexed to an abasic site containing DNA exhibit a common disordered region present in the C-terminal domain of the enzyme. However, this region is believed to be involved in the damaged base binding site when the initial protein/DNA complex is formed. The dynamic behavior of the disordered polypeptide (named Loop) in relation to the supposed scenario for the DNA repair mechanism was investigated by molecular dynamics on different models, derived from the X-ray structure of Lactococcus lactis Fpg bound to an abasic site analog-containing DNA and of Bacillus stearothermophilus Fpg bound to 8-oxoG. This study shows that the presence of the damaged base influences the dynamics of the whole enzyme and that the Loop location is dependent on the presence and on the conformation of the 8-oxoG in its binding site. In addition, from our results, the conformation of the 8-oxoG seems to be favored in syn in the L. lactis models, in agreement with the available X-ray structure from B. stearothermophilus Fpg and with a possible catalytic role of the flexibility of the Loop region.

Keywords: molecular dynamics; DNA repair; 8-oxoguanine; Fpg

Abbreviations: AP, apuric • 8-oxoG, 8-oxoguanine • L. lactis, X-ray structure of Fpg from Lactococcus lactis bound to an abasic site analog-containing DNA • Loop, residues 217–225 in L. lactis and corresponding residues in other Fpgs • freein, freeout, oxosynin, oxosynout, and oxoantiin, theoretical models derived from L. lactis with different conformations of the Loop, orienting Tyr 222 inside ("in") or outside ("out") the cavity, free or 8-oxoG-bound in syn or anti • B. stearothermophilus, X-ray structure of Fpg from Bacillus stearothermophilus bound to an 8-oxoG-containing DNA • bsoxo, theoretical model derived from B. stearothermophilus • T. thermophilus, X-ray structure of Fpg from Thermus thermophilus • MD, molecular dynamics • rmsd, root mean square deviation

Reprint requests to: Patricia Amara or Laurence Serre, Institut de Biologie Structurale Jean-Pierre Ebel CEA/CNRS/UJF, 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France; e-mail: amara{at}ibs.fr or serre{at}ibs.fr; fax: 33-4-38785494.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04772404.

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