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

Czeleń P, Cysewski P - J Mol Model (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Physical Chemistry Department, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-950 Bydgoszcz, Poland. przemekcz@cm.umk.pl

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Time evolution of enthalpic contribution (∆H) to Gibbs free energy of the studied native and oxidized telomeric complexes
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3713266&req=5

Fig2: Time evolution of enthalpic contribution (∆H) to Gibbs free energy of the studied native and oxidized telomeric complexes

Mentions: The time evolution of enthalpic and entropic contributions to Gibbs free energy was also determined. The data plotted in Figs. 2 and 3 indicate unambiguously that the distributions of ΔH and ΔS values for native and oxidized systems are entirely different. During the simulation, numerous intervals characterized by enthalpy deviations as high as 30 kcal mol−1 were observed. Interestingly, the discrepancy between the entropic contributions to Gibbs free energy of S1 and S2 becomes more significant with longer time of simulation suggesting that the observed trend is rather persistent. The systematic rise in energy up to 10 kcal mol−1 clearly indicates the decrease in stability of the oxidized complex. The observed differences in global values of Gibbs free energy have their origin in the numerous changes reported for individual interactions localized in the space of the major groove.Fig. 2


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

Czeleń P, Cysewski P - J Mol Model (2013)

Time evolution of enthalpic contribution (∆H) to Gibbs free energy of the studied native and oxidized telomeric complexes
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3713266&req=5

Fig2: Time evolution of enthalpic contribution (∆H) to Gibbs free energy of the studied native and oxidized telomeric complexes
Mentions: The time evolution of enthalpic and entropic contributions to Gibbs free energy was also determined. The data plotted in Figs. 2 and 3 indicate unambiguously that the distributions of ΔH and ΔS values for native and oxidized systems are entirely different. During the simulation, numerous intervals characterized by enthalpy deviations as high as 30 kcal mol−1 were observed. Interestingly, the discrepancy between the entropic contributions to Gibbs free energy of S1 and S2 becomes more significant with longer time of simulation suggesting that the observed trend is rather persistent. The systematic rise in energy up to 10 kcal mol−1 clearly indicates the decrease in stability of the oxidized complex. The observed differences in global values of Gibbs free energy have their origin in the numerous changes reported for individual interactions localized in the space of the major groove.Fig. 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Physical Chemistry Department, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-950 Bydgoszcz, Poland. przemekcz@cm.umk.pl

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus