Molecular dynamics of d(CGCGAATTCGCG)2 complexed with netropsin and its minor groove methylating analog, Me-lex, using explicit and implicit water models

Me-lex, {1-methyl-4-[1-methyl-4-[3-(methoxysulfonyl)-propanamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido}-propane}, a neutral methyl sulfonate analog of netropsin lacking the cationic tails, methylates adenines in the minor groove of DNA at the same A/T rich sequences targeted by netropsin, suggesting that minor groove recognition at A/T sequences can be achieved without the ionic and hydrogen bonding interactions involving the tails of such molecules. Molecular dynamics simulations have been performed on the complexes of the Dickerson-Drew dodecamer, d(CGCGAATTCGCG), with Me-lex and netropsin and their binding interactions have been compared. Simulations have been conducted with an explicit solvent model and the Generalized Born (GB) implicit solvent model. The central bispyrrole triamide unit in both molecules establish similar interactions within the groove. The propyl and methyl sulfonate tails of Me-lex exhibit significant conformational flexibility, and the propyl group causes large variations in the minor groove width in its vicinity. Results obtained using the GB model are very similar to those obtained using the explicit water model. Therefore the computationally efficient GB model can be used to investigate interactions in such systems over longer time scales.