Structural and energetic consequences of oxidation of d(ApGpGpGpTpT) telomere repeat unit in complex with TRF1 protein

2010

J Mol Model

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Non-additivity of base-base interactions in all ten possible model dinucleotide steps were analyzed on MP2/aug-cc-pvDZ quantum chemistry level. Selected conformations of four nucleobases exactly matched to ones occurring in B-DNA crystals. In most of 162 analyzed tetramers both threeand four-body contributions are negligible except of d(GpG) steps. However, in these dinucleotides both contributions are always of opposite signs and in all cases the sum of all non-additive part of intermolecular interactions do not exceed 2.6 kcal/mol. This stands for less than 5% of the overall binding energy of dinucleotide steps. Also replacements of guanine with 8-oxoguanine in d(GpG) systems introduces non-additivity of the same magnitude as for canonical dinucleotides. It is observed linear relationships between values of the total binding energy obtained in the tetramer basis set and estimated energy exclusively in dimers basis sets with assumption of pairwise additivities. For all analyzed dinucleotides steps there are also linear correlations between amount of non-additive contributions and magnitude of pairs interactions. Based on differences in electrostatic contribution to the total binding energy of four nucleobases and polarity of dinucleotide steps three distinct classes of dinucleotide steps were identified.Response to Reviewers: 1) I recommend to do a careful proofreading, there are many typos and some sentences are difficult to understand. Thank you. Careful proofreading was applied and text was modified accordingly.2) Page 3, Results and discussion Alltogether 162 dinucleotide steps were analyzed. The number of individual steps is variable, why is it so? Why there was 48 d(GpG) steps, but only 10 d(GpC) steps? What were the PDB codes of structures from which steps were chosen, and which steps (chain ID, res ID) were chosen? What was the resolution of these structures? This information could go to the Supplementary material.In supplementary material details related to analyzed structures are provided now. The differences in dinucleotide populations have strictly technical reason. Since in my previous work accepted for publication in Int.J.Quantum Chem. (DOI:10.1002/qua.22435) detailed analysis of d(GpG) steps were presented I have just included these data in this work. Consequently this dinucleotide is overrepresented. Since it constitutes its own class I do not think that such overrepresentation changes papers conclusions. On the other hand it is not necessary extending the number of other dinucleotide steps since the non-additivity is quite small and they were selected from broad range of data according to IIE and structural parameters diversities.3) Page 3, Results and discussion The numbers of steps are large enough to perform some statistical analysis of resulting energies. E.g. ANOVA could be performed to test whether the mean energies in dinucleotide steps differ significantly each from other. Also, is the distribution of energies for individual steps Gaussian or not? If not, some non-parametric ...

Section: Additivity Of Interactions In Dinucleotide Steps Comprising mentioning

confidence: 99%

Section: Additivity Of Interactions In Dinucleotide Steps Comprising mentioning

confidence: 99%

Non-additive interactions of nucleobases in model dinucleotide steps occurring in B-DNA crystals

2010

J Mol Model

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“…Moreover, since GG and GGG stacked guanine sequences have lower IPs than single guanines [24, 27], such sequences are even more probable sites for undergoing oxidation. Also, formation of complexes by telomeric sequences with telomeric repeat binding factor (TRF) protein ligands is affected greatly by the presence of oxidative damage in the guanine triad [28, 29]. The appearance of a single 8-oxoguanine molecule decreases binding affinity between DNA and protein by about 50 %, while the presence of multiple 8-oxoguanine molecules in the telomeric sequence completely disrupts binding [30–32].…”

Section: Introductionmentioning

confidence: 99%

“…The appearance of a single 8-oxoguanine molecule decreases binding affinity between DNA and protein by about 50 %, while the presence of multiple 8-oxoguanine molecules in the telomeric sequence completely disrupts binding [30–32]. The most important changes related to the presence of the 8-oxoguanine molecule in telomeric sequences are observed in the space of the major groove [28, 29, 33], which plays the role of an active site responsible for binding of protein ligands. Figure 1 presents the structure of single subunit formed by one telomeric sequence and TRF1 protein ligand.…”

Section: Introductionmentioning

confidence: 99%

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Structural and energetic properties of canonical and oxidized telomeric complexes studied by molecular dynamics simulations

Czeleń

2013

J Mol Model

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The structural and energetic properties of native and oxidized telomeric complexes were defined by means of molecular dynamic (MD) simulations. As a starting point, the experimental conformation of B-DNA d(GpTpTpApGpGpGpTpTpApGpGpG) oligomer bound to human protein telomeric repeat binding factor 1 (TRF1) was used. The influence on the stability of the telomeric complex of the presence of 8-oxoguanine (8oxoG) in the central telomeric triad (CTT) was estimated based on trajectories collected during 130 ns MD runs. The data obtained indicate that the system analyzed is highly sensitive to the presence of oxidative damage in the CTT of the B-DNA telomeric sequence. The most important changes were observed in the immediate vicinity of the 8-oxoguanine molecule. The significantly higher mobility of arginine 425 interacting directly with the oxidized guanine molecule has a large influence on the structural, dynamic and energetic properties of neighboring amino acids. Local changes observed for individual hydrogen bonded interactions localized in the major groove of B-DNA also have significant impact on the properties of hydrophobic clusters, which are the second type of force responsible for stability of the studied bio-system. All the changes reported in detail here unambiguously indicate a significant decrease in telomer binding affinity after oxidation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-013-1859-z) contains supplementary material, which is available to authorized users.

Structural, electronic and energetic consequences of epigenetic cytosine modifications

Phys. Chem. Chem. Phys.

Oliński

2015

The hydrogen bonding patterns of cytosine and its seven C5-modifed analogues paired with canonical guanine were studied using the first principle approach. Both global minima and biologically relevant conformations were studied. The former resulted from full gradient geometry optimizations of hydrogen bonded pairs, while the latter were obtained based on 125 d(GpC) dinucleotides found in the PDB database. The obtained energetic, electronic and structural data lead to the conclusion that the epigenetically relevant modification of cytosine may have serious consequences on hydrogen bonding with guanine. First of all, the significant substituent effects were observed for such trends as charges on sites involved in hydrogen bonding, the total intermolecular interaction energy or electron densities at bond critical points. Moreover, the molecular orbital polarization contribution resulting from energy decomposition expressed in terms of absolutely localized molecular orbitals exhibited an inverse linear correlation with frozen density contributions. A substituent effect on the amount of charge transfer from pyrimidine toward guanine was also observed. The increase of intermolecular interactions of guanine with modified cytosine is associated with the increase of the electro-donating character of the C5-substituent. However, only pairs involving 5-methylcytosine are more stable than those formed by canonical cytosine. Furthermore, the energy differences observed for global minima also remain important for a broad range of displacement and angular parameters defining pair conformations in model d(GpC) dinucleotides. Due to the sensitivities of intermolecular interactions to mutual arrangements of monomers the modification of cytosine at the C5 site can significantly alter the actual energy profiles. Consequently, it may be anticipated that the modified dinucleotides will adopt different conformations than a standard G-C pair in a B-DNA double helix.