Anthracycline-binding induced Dna stiffenin, bending and elongation; stereochemical implications from viscometic investigations

Abstract

Upon interaction of the three anthracycline antibiotics daunomycin, adriamycin, and aclacinomycin A with calf thymus DNA the relative changes of both DNA contour length, delta L/Lo, and persistence length, delta a/ao, have been determined as a function of r, the ratio of bound ligand molecules per DNA mononucleotide. From the r dependence of delta a/ao a measure for the stiffening effect and also the angle gamma of ligand-induced DNA bending could be derived. Experimental basis are titration viscometric measurements upon both low and high molecular weight DNA. It was found that the DNA contour length increases linearly with r by approximately 0.34 nm per bound drug molecule. The comparatively very high DNA stiffening effect measured in solution is understandable as a result of helix clamping by at least two anthracycline groups of sufficient long distance. The variation of gamma on DNA interaction with different anthracycline derivatives find their explanation in terms of different values of the mismatch to in-register binding prior to complex formation. From an analogous interpretation of viscosity measurements by Arcamone and coworkers upon high molecular weight DNA with many anthracycline derivatives it can be concluded that DNA interaction by both amino sugar and 9-acetyl group are responsible for the generation of strong anthracycline binding mediated DNA stiffening effects in solution. (A combined analysis of the viscosity measurements by Cohen & Eisenberg and Armstrong et al. upon DNA interaction with proflavine indicates a very small DNA stiffening effect, gamma = 6.7 sigma and a helix elongation by 0.35 nm per bound ligand molecule.)

DNA interaction with DAPI fluorescent dye: Force spectroscopy decouples two different binding modes

“…Observe that in both cases the persistence length presents a simple monotonic decrease as a function of the DAPI concentration. [2,20] Such result was also obtained by authors that use non-stretching (zero force) techniques, [21,[23][24][25][26][27][28] although experiments performed in a higher force regime can lead to different results. [9,15,21,22] Such result strongly suggests that groove binding is the main mode of interaction between DAPI and k-DNA, a conclusion also achieved by these cited works.…”

“…In fact, recently we have shown that intercalation in general increases the DNA persistence length when measured in the force regime < 2 pN. [2,20] Such result was also obtained by authors that use non-stretching (zero force) techniques, [21,[23][24][25][26][27][28] although experiments performed in a higher force regime can lead to different results. [29,30] DAPI is a divalent cationic (21) molecule [9] (see Figure 1), and therefore neutralizes significantly the negative phosphate backbone of the double-helix.…”

1H NMR structural and thermodynamical analysis of complexation of propidium iodide with deoxytetranucleotide 5'-d(TpGpCpA) in aqueous solution

“…Значительный вклад гидрофобных взаимодействий наблюдается в случае реакции образования комплекса 1:2 PI с дуплексом d(TGCA), характеризуемой существен но меньшим абсолютным значением энтропии в сравнении с другими комплексами «красительтетрануклеотид», образующимися в растворе. В случае же комплекса состава 2:2, когда две моле кулы лиганда интеркалируют в дуплекс, несколько большие отрицательные значения АН и AS по сравнению с комплексом состава 1:2 могут быть обусловлены увеличением жесткости спиральной структуры, что дополнительно к дисперсионным взаимодействиям между молекулами приводит к уменьшению энтальпии и энтропии при формиро вании комплекса [21 ].…”

DNA-Helix Bending, Stiffening and Elongation on Ligand Binding; Analysis for Serveral DNA-Drug Systems, General Viscometric DNA Response and Stereochemical Implications

“…sequenceindependent, and their values seem to be near 0.2nm and go, respectively. For the interaction of the clinically applied anticancer drug daunomycin (Dau) with calf thymus DNA, ~y 1 (r) and ~yh(r) have been measured in this laboratory (33). The results are summarized in the insert of Figure The apparent dependences of ~L/L o on r, as calculated only from ~ylr) for the DNA sample of low molar mass by means of three different approaches which neglect the non-rigidity of DNA (2,3,34), are also given in Figure 2A It is characteristic for these approximations that the curves are non-linear, and also that the mean deviation from our linear curve decreases with improving adequateness of the respective calculus (49).…”

“…A formal determination of the helix-bending angle y by means of Equations (6a,bl with cr= 1 results in y=9.9o [ref. (33) . We find, for the two orders of magnitude in Mr between 0.23 X 10 6 and 24 X 10 6 , that the r dependent DNA conformational changes presented in the insert describe the rather "unusual" character of the DNA viscosity changes for this DNA complex in a fairly consistent manner.…”