Abstract
DNA bending caused by introduction of carbocyclic sugars constrained to the north conformation was studied, using explicit solvent molecular dynamic (MD) simulations. The native Drew-Dickerson (DD) dodecamer and its three modifications containing north carbocyclic sugars in the 7th (T7*), 8th (T8*) or both 7th and 8th (T7T8*) nucleotide positions were examined. Introduction of the carbocyclic sugar results in A-form conformations for the alpha, beta, chi, zeta, and sugar pucker backbone parameters in the modified nucleotides. Increased steric repulsion between the sugar and its parent base in the modified oligonucleotides impacts the roll and cup dinucleotide step parameters, increasing the bending of the oligomer axis. Increased buckling of the substituted nucleotides disrupts the usual stabilizing base stacking interactions. The level of overall bending depends on the number and position of carbocyclic sugars introduced in the DNA sequence. Single sugar substitutions are unable to induce substantial bending due to the neighboring unmodified nucleotides counterbalancing the distortion. Significant bending can, however, be induced by two consecutive north sugars (T7T8*), which is in agreement with experimental results. The modified oligomers populate a wide range of bend angles, indicating that they maintain flexibility in the bent state. The present results suggest that insertion of carbocyclic sugars into DNA or RNA duplexes can be used to engineer bending of the duplexes without impacting the electrostatic or chemical properties of the phosphodiester backbone, thereby serving as excellent tools for experimental elucidation of nucleic acid structure-function relationships.