Molecular Dynamics Studies of DNA A-Tract Structure and Flexibility

Molecular dynamics simulations have been used to compare the structure and dynamics of three A-tract-containing DNA dodecamer sequences: d(CGCAAATTTGCG)2, d(CGCAIATMTGCG)2, and d(CGCIIIMMMGCG)2, where M = 5-methylcytosine. The simulations shed light on experimental observations regarding DNA bending induced by these sequences. We find that replacing an A•T base pair by an I•M base pair does far more to the structure and particularly dynamics of the oligonucleotides than might be expected if the substitution were regarded as just exchanging a hydrogen bond donor and acceptor across the DNA major groove. The evaluation of the molecular dynamics data is greatly simplified by the application of the method of principal component analysis. This allows key differences in the structures and dynamics of the three systems to be readily discerned. Three major modes of deformation are observed, the amplitudes and/or average values of which can vary with sequence. The results allow a simple interpretation of the effects of A•T to I•M substitutions on DNA bending and point to the importance of DNA flexibility, as much as static structure, in determining macroscopic behavior.