Complex of B-DNA with polyamides freezes DNA backbone flexibility

The development of sequence-specific minor groove binding ligands is a mode rn and rapidly growing field of research because of their extraordinary imp ortance as transcription-controlling drugs. We performed three molecular dy namics simulations in order to clarify the influence of minor groove bindin g of two ImHpPyPy-beta -Dp polyamides to the d(CCAGTACTGG)(2) decamer in th e B-form. This decamer contains the recognition sequence for the trp repres sor (5 ' -GTACT-3 '), and it was investigated recently by X-ray crystallogr aphy. On one hand we are able to reproduce X-ray-determined DNA-drug contac ts, and on the other hand we provide new contact information which is impor tant for the development of potential ligands. The new insights show how th e P-tail of the polyamide ligands contributes to binding. Our simulations a lso indicate that complexation freezes the DNA backbone in a specific B-I o r B-II substate conformation and thus optimizes nonbonded contacts. The exi stence of this distinct B-I/B-II substate pattern also allows the formation of water-mediated contacts. Thus. we suggest the B-I reversible arrow B-II substate behavior to be an important part of the indirect readout of DNA.