Structural and energetic consequences of oxidation of d(ApGpGpGpTpT) telomere repeat unit in complex with TRF1 protein.
The configuration hyperspace of canonical and oxidized 14-mers of B-DNA comprising telomere repeat units d(ApGpGpGpTpT) was sampled over 40 ns via molecular dynamic (MD) simulations. The energetic and structural consequences of TRF1 binding to telomere B-DNA were compared with non-complexed systems. Energetic properties of analyzed pairs, di- and tri-nucleotide steps occurring in central telomere repeat unit were estimated by means of advanced quantum chemistry computations including not only BSSE corrections, electron correlation contributions but also non-negligible many-body terms. These data along with bases pair and base step parameters distributions allow for quantization of consequences of oxidation and/or TRF1 binding to telomere repeat units. Occurrence of 8-oxoguanine in central telomeric triad (CTT) is the source of high stiffness if compared to non-modified oligomer. The origin of this property comes from significantly alteration of intermolecular interactions introduced by 8-oxoguanine. The increased stability observed for base-base interactions are accumulated and characterizes also di- and tri-nucleotides. The observed changes in the intermolecular interactions originate from structural alterations imposed by TRF1 binding to canonical and oxidized telomere B-DNA. First and most direct consequence of TRF1 binding to oxidized telomere repeat unit is alteration of shift-slide correlations if compared to canonical system. This in turn leads to large differences in purine-purine overlapping in oxidized structures. Thus, oxidized telomere B-DNA double strands are sensitive to interactions with protein ligands and numerous structural and energetic changes are imposed on base pairs forming CTT.
Cysewski
Piotr
P
Physical Chemistry Department, Collegium Medicum, Nicolaus Copernicus University, Kurpińskiego 5, 85-950, Bydgoszcz, Poland. piotr.cysewski@cm.umk.pl
Czeleń
Przemysław
P
D001483:Base Sequence; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011485:Protein Binding; D011687:Purines / Q000378:metabolism; D012044:Regression Analysis; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D016615:Telomere / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D011687:Purines; D035321:Telomeric Repeat Binding Protein 1
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