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Article

Structural and Thermodynamic Studies of the Interaction of Distamycin A with the Parallel Quadruplex Structure [d(TGGGGT)]₄

Supporting Info

Luigi Martino,^† Ada Virno,^‡ Bruno Pagano,^§ Antonella Virgilio,^‡ Simone Di Micco,^§ Aldo Galeone,^‡ Concetta Giancola,^† Giuseppe Bifulco,^§ Luciano Mayol,^‡ and Antonio Randazzo*^‡

Contribution from the Dipartimento di Chimica P. Corradini, Universit degli Studi di Napoli Federico II, via Cintia, I-80126, Napoli, Italy, Dipartimento di Chimica delle Sostanze Naturali, Universit degli Studi di Napoli Federico II, via D. Montesano 49, I-80131 Napoli, Italy, and Dipartimento di Scienze Farmaceutiche, Universit di Salerno, via Ponte Don Melillo, 84084, Fisciano (SA), Italy

J. Am. Chem. Soc., 2007, 129 (51), pp 16048–16056

DOI: 10.1021/ja075710k

Publication Date (Web): December 4, 2007

†

Dipartimento di Chimica “P. Corradini”, Università degli Studi di Napoli “Federico II”.

‡

Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli “Federico II”.

Dipartimento di Scienze Farmaceutiche, Università di Salerno.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, antonio.randazzo@unina.it

Abstract

The complex between distamycin A and the parallel DNA quadruplex [d(TGGGGT)]₄ has been studied by ¹H NMR spectroscopy and isothermal titration calorimetry (ITC). To unambiguously assert that distamycin A interacts with the grooves of the quadruplex [d(TGGGGT)]₄, we have analyzed the NMR titration profile of a modified quadruplex, namely [d(TGG^MeGGT)]₄, and we have applied the recently developed differential frequency-saturation transfer difference (DF-STD) method, for assessing the ligand−DNA binding mode. The three-dimensional structure of the 4:1 distamycin A/[d(TGGGGT)]₄ complex has been determined by an in-depth NMR study followed by dynamics and mechanics calculations. All results unequivocally indicate that distamycin molecules interact with [d(TGGGGT)]₄ in a 4:1 binding mode, with two antiparallel distamycin dimers that bind simultaneously two opposite grooves of the quadruplex. The affinity between distamycin A and [d(TGGGGT)]₄ enhances (10-fold) when the ratio of distamycin A to the quadruplex is increased. In this paper we report the first three-dimensional structure of a groove-binder molecule complexed to a DNA quadruplex structure.