Stereochemical effects of non-ionic methylphosphonates on nucleotide conformations

Abstract

The preferred conformations of deoxyribo and ribonucleoside 3′-methylphosphonates are analysed by minimizing the conformational energy as a function of all the major parameters including the sugar ring for both the S- and R-isomers. The results show that neither the substitution nor the nature of the diastereomer affects significantly the preferred conformations compared to the naturally occurring nucleoside 3′-phosphates. The preferred range of Cṫ'-03′ bond torsions or the phase angles of pseudorotation (P) of the sugar are unaffected. The chiral substitution on the phosphate always adopts a conformation distal to the secondary C3′ carbon atom in the minimum energy conformational state. Further, it introduces certain restrictions on the preferred range of P-03′ torsions depending on the methylphosphonate configuration. Methylphosphonate, especially the S-isomer, renders the normal gauche − range of P-′03 bond torsions responsible for the stacked helical duplexes to be energetically unfavourable besides introducing a high energy barrier between trans and gauche conformations. Therefore it is suggested that duplexes with S-methylphosphonate may favour extended phosphodiester conformations. These factors explain the observed lower melting temperature as well as the downfield shifts in the 31P signals in duplexes containing the S-isomer.