Influence of 8-Oxoguanosine on the Fine Structure of DNA Studied with Biasing-Potential Replica Exchange Simulations

Abstract

Chemical modification or radiation can cause DNA damage, which plays a crucial role for mutagenesis of DNA, carcinogenesis, and aging. DNA damage can also alter the fine structure of DNA that may serve as a recognition signal for DNA repair enzymes. A new, advanced sampling replica-exchange method has been developed to specifically enhance the sampling of conformational substates in duplex DNA during molecular dynamics (MD) simulations. The approach employs specific biasing potentials acting on pairs of pseudodihedral angles of the nucleic acid backbone that are added in the replica simulations to promote transitions of the most common substates of the DNA backbone. The sampled states can exchange with a reference simulation under the control of the original force field. The application to 7,8-dihydro-8oxo-guanosine, one of the most common oxidative damage in DNA indicated better convergence of sampled states during 10 ns simulations compared to 20 times longer standard MD simulations. It is well suited to study systematically the fine structure and dynamics of large nucleic acids under realistic conditions, including explicit solvent and ions. The biasing potential-replica exchange MD simulations indicated significant differences in the population of nucleic acid backbone substates in the case of 7,8-dihydro-8oxo-guanosine compared to a regular guanosine in the same sequence context. This concerns both the ratio of the B-DNA substates B(I) and B(II) associated with the backbone dihedral angles ε and ζ but also coupled changes in the backbone dihedral angles α and γ. Such differences may play a crucial role in the initial recognition of damaged DNA by repair enzymes.

Global deformation facilitates flipping of damaged 8-oxo-guanine and guanine in DNA

“…Previous unrestrained MD simulations of dsDNA oligonucleotides with a central G:C or 8oxoG:C base pair indicated differences in the DNA fine structure but no spontaneous extrusion or flipping of the damaged guanine on the time scale (hundreds of ns) of current MD simulations (13). In order to compare the free energy required to flip a regular undamaged guanine and an oxidized 8oxoG umbrella sampling free energy simulations along a pseudo dihedral reaction coordinate were performed.…”

“…Although the presence of the 8oxoG damage can lead to changes in the fine structure and dynamics of DNA (13–15) the overall structure of isolated 8oxoG containing duplex DNA is very similar to undamaged DNA. In addition, the thermal stability of 8oxoG–DNA is similar to regular duplex DNA of the same sequence (16–19).…”

Conformational Sampling of Oligosaccharides Using Hamiltonian Replica Exchange with Two-Dimensional Dihedral Biasing Potentials and the Weighted Histogram Analysis Method (WHAM)

“…Traditionally, only the ground-state, unbiased replica is used for data analysis. 15, 17, 50-51, 62-63 In this study, we propose to combine all the replicas with the weighted histogram analysis method (WHAM) to obtain an optimal distribution under the original potential of the system. Following the original WHAM 64 implementation, the probability distribution from H-REX can be expressed as the combination of the distribution from each replica, 64-65 …”

Coupled binding–bending–folding: The complex conformational dynamics of protein-DNA binding studied by atomistic molecular dynamics simulations

“…Another area of interest is the bending of mismatched [96,97], damaged [98,99], or modified DNA. Of particular interest is DNA with methylated cytosines, which serve as epigenetic markers [100][101][102].…”