Stereochemical effects of methylphosphonate in B- and Z-DNA helices: variation in hydrophobicity and effective widths of grooves.

Stereochemical effects of methylphosphonate (MP) in B-DNA and Z-DNA duplexes are studied through molecular mechanics approach. Duplexes of different lengths, tetramers, hexamers, dodecamers are examined to assess the interstrand and intrastrand electrostatic effects due to MPs vis-a-vis phosphates. A variety of models which include duplexes with alternating S-MP and R-MP, alternating phosphate and MP and, duplexes possessing MPs in only one of the strands, are examined by considering both the S- and R-stereoisomers. Majority of the calculations are performed with CG sequences to delineate factors responsible for the stability of B- and Z-DNA, as well as B-->Z-DNA transition under nonionic conditions. The results show that both B- and Z-DNA duplexes are energetically favoured in the presence of MP due to overwhelming reduction in intrastrand as well as interstrand electrostatic repulsive interactions. The effect is distinct in oligomers longer than tetramers. Comparison of energetics of MP B- and Z-DNA duplexes suggests that an oligodeoxynucleotide such as d(CG)6 with all phosphates replaced by MPs may favour equally both B- and Z-DNA conformations. The analysis further provides an estimate of electrostatic interactions, operating at the grooves under a variety of conditions. Several specific and localised effects due to S-MP and R-MP are seen at CG and GC steps in various B-DNA and Z-DNA models. S-MP in B-DNA reduces the effective major groove width by nearly 3 A hence denying access to the functional groups of endonucleases thereby enhancing the resistance of MP-DNA to enzymatic digestion. Further, methyl groups of MP render the surface of the DNA helix to be significantly hydrophobic which may explain higher permeability of MP-DNA in membranes as well as its less soluble nature in aqueous media.