BII stability and base step flexibility of N6-adenine methylated GATC motifs

Abstract

The effect of N6-adenine methylation on the flexibility and shape of palindromic GATC sequences has been investigated by molecular dynamics simulations. Variations in DNA backbone geometry were observed, which were dependent on the degree of methylation and the identity of the bases. While the effect was small, more frequent BI to BII conversions were observed in the GA step of hemimethylated DNA. The increased BII population of the hemimethylated system positively correlated with increased stacking interactions between methylated adenine and guanine, while stacking interactions decreased at the TC step for the fully methylated strand. The flexibility of the AT and TC steps was marginally affected by methylation, in a fashion that was correlated with stacking interactions. The facilitated BI to BII conversion in hemimethylated strands might be of importance for SeqA selectivity and binding.

Biasing Simulations of DNA Base Pair Parameters with Application to Propellor Twisting in AT/AT, AA/TT, and AC/GT Steps and Their Uracil Analogs

“…Since DNA bases are planar and rigid, the shape of DNA is well-described by the relative orientation of bases within a base pair and the relative orientation of adjacent bases. , Of these, the base parameters describe the rigid body rotations and translations of bases within a base pair, and the step parameters describe the rigid body rotations and translations of adjacent base pairs . Step parameters have previously served as order parameters in biasing simulations of DNA, yielding important insights into the flexibilities of normal, damaged, and methylated DNA, , and into DNA bending − and its role in binding. , Here we will describe an efficient and robust way to calculate base parameters and their spatial derivatives for use in biasing simulations. This method prevents the expense of least-squares fitting procedures such as ideal base pair overlays and base pair plane fitting which are part of the standard base parameter definitions .…”

“…16,17 Of these, the base parameters describe the rigid body rotations and translations of bases within a base pair, and the step parameters describe the rigid body rotations and translations of adjacent base pairs. 17 Step parameters have previously served as order parameters in biasing simulations of DNA, 18 yielding important insights into the flexibilities of normal, 18 damaged, 19 and methylated DNA, 18,20 and into DNA bending 21−23 and its role in binding. 24,25 Here we will describe an efficient and robust way to calculate base parameters and their spatial derivatives for use in biasing simulations.…”

A framework for mutational signature analysis based on DNA shape parameters

“…Such structural parameters are considered to be an accurate description of DNA conformation, summarizing atomic coordinates of nucleotides in a compact representation [ 32 – 34 ]. DNA susceptibility to mutagenic agents or recognition by DNA repair enzymes might be enhanced or disrupted by genetic differences in the regions flanking the mutation site [ 35 , 36 ]. Because DNA predictably acquires a sequence-dependent local conformation, this provides a rationale for implementing sequence-derived DNA shape parameters into a framework to predict and classify mutagenic processes.…”

A framework for mutational signature analysis based on DNA shape parameters

“…29–31 Because DNA predictably acquires a sequence-dependent local conformation, DNA susceptibility to mutagenic agents or recognition by DNA repair enzymes might be enhanced or disrupted by genetic differences in the regions flanking the mutation site. 32,33 This provides a rationale for implementing DNA shape parameters into a framework to predict and classify mutagenesis.…”

“…32–34 DNA susceptibility to mutagenic agents or recognition by DNA repair enzymes might be enhanced or disrupted by genetic differences in the regions flanking the mutation site. 35,36 Because DNA predictably acquires a sequence-dependent local conformation, this provides a rationale for implementing sequence-derived DNA shape parameters into a framework to predict and classify mutagenic processes.…”