CTAG vs. GATC: Structural Basis for Representational Differences in Reverse Palindromic DNA Tetranucleotide Sequences

Abstract

Genomic compositional biases are broadly acknowledged. For example, the tetranucleotide CTAG is extraordinarily rare in almost all bacterial, archaeal, eukaryotic genomes and some phage genomes. Moreover, CTAG is remarkably underrepresented relative to its reverse palindromic sequence GATC. To determine the origin of compositional biases, we analyze structural features of palindromic DNA duplexes derived in all-atom molecular simulations. We answer this question by comparing the structural features of 12-mer DNA duplexes comprising a central tetramer sequence of CTAG, GATC, and CGCG. This study uses unbiased and biased molecular dynamics simulations to compare the torsional angles of dinucleotides in a DNA duplex. Specifically, we use all-atom molecular dynamics and well-tempered metadynamics simulations to produce trajectories of the torsion angles between dinucleotides in the sequence and calculate the free energy surfaces using torsional collective variables. The data show a correlation between the sequence and the degree of the duplex unwinding. More significantly, data show that the CTAG sequence has a more unwinding effect on the DNA duplex than the GATC sequence. This conclusion suggests that the CTAG sequence bases are more accessible from the minor groove surface than the GATC bases. Consequently, the CTAG sequence appears more exposed to chemical modifications which may explain its extreme underrepresentation in the bacterial genome.