Molecular modeling study of the effect of base methylation on internal interactions and motions in DNA and implication to B-Z conformation change

1. Introduction Experimental studies have shown that a DNA molecule with alternating pyrimidine-purine sequence can adopt a left-handed, double-helical Z-DNA conformation [1,2]. Such structural changes of DNA occur as a consequence of environmental conditions such as at salt concentration above 4 mol/L NaCl [1,2] or through certain chemical modification such as methylation [1] or bromination [2,3] of bases at physiological conditions. These structural changes and chemical modifications …

Molecular modeling study of the effect of base methylation on internal interactions and motions in DNA and implication to B-Z conformation change

Methylation in the bases of DNA is known to induce B-Z conformation change. In this work, molecular mechanics and normal mode analysis are used to probe how certain methylation affects the internal interactions and thermodynamic motions in the DNA double helixes in both B and Z conformations, and its implication to B-Z conformation change. By molecular modeling with Insight II, two cases involving cytosine C5 and guanine C8 methylation on both B and Z-form DNA duplex d(CGCGCG)2 are studied in comparison with the corresponding unmethylated duplexes. The internal interaction energies computed based on a molecular mechanics force field and the entropies due to internal motions computed according to a normal mode analysis are in fare agreement with respective observed thermodynamic quantities. The analysis on the computed individual energy terms suggests that the observed B-Z conformation change induced by methylation is primarily driven by enthalpic factors. A combination of changes in Van der Waals interaction, electrostatic interaction and hydrogen bonding likely contributes to the change of enthalpy that favors Z-conformation in the methylated states.