Theoretical Study of Sequence Selectivity and Preferred Binding Mode of Psoralen with DNA

Abstract

Psoralen interaction with two models of DNA was investigated using molecular mechanics and molecular dynamics methods. Calculated energies of minor groove binding and intercalation were compared in order to define a preferred binding mode for the ligand. We found that both binding modes are possible, explaining the low efficiency for monoadduct formation from intercalated ligands. A comparison between the interaction energy for intercalation between different base pairs suggests that the observed sequence selectivity is due to favorable intercalation in 5′-TpA in (AT)n sequences.

DNA interstrand crosslink repair in mammalian cells: step by step

“…Psoralens intercalate into DNA with a preference for 5'TA steps (Sinden and Hagerman, 1984) (Saenz-Méndez et al , 2007) and runs of (TA) are hotspots for modification (Boyer et al , 1988). Formation of an ICL proceeds via a two step, two photon reaction.…”

Photoreactivity of Furocoumarins and DNA in PUVA Therapy: Formation of Psoralen−Thymine Adducts

“…6,49 Taking into account that 3-CPS is also considered a productive source of singlet oxygen for PDT therapy [6][7][8][9][10] and that khellin has been recently suggested as the most efficient photosensitizer among a number of furocoumarins, 41 both 3-CPS and khellin are plausible candidates to substitute in the PUVA therapy to the widely employed 8-MOP. 50 From the theoretical standpoint, studies have been only focused on the intercalation of the photosensitizer between the π-stacked nucleobases, using classical mechanics approaches, 16 and in the determination of the ground-state structures of the adducts, at the semiempirical [51][52][53][54][55] or ab initio single-reference RHF, DFT, MP2, and CCSD(T) levels. 56 The complexes have been determined much more stable in the noncoplanar trans than in the stacked cis arrangements (see Figure 2).…”

“…Recent molecular dynamics computations show that psoralen photoreacts preferably in [AT] n sequences . As in other DNA−drug interactions, getting the proper geometric alignment is a relatively low-efficiency process because of the existence of two competitive noncovalent interaction mechanisms: on the one hand, the intercalation of the furocumarin between two nucleobases that gives rise to the photoreaction, and, on the other hand, its association with the minor groove binding of DNA. , Following irradiation with UVA light, photoadditions occur either at the C 4′ C 5′ bond of the furan moiety of the furocoumarin (to form furan monoadducts, FMA) or at the C 3 C 4 bond of the pyrone moiety (to form pyrone monoadducts, PMA) (see Figure ). The monoadduct may absorb another photon, inducing the other photoreactive CC double bond to interact with a thymine on the opposite DNA strand and producing a diadduct that cross-links the DNA helix.…”

“…From the theoretical standpoint, studies have been only focused on the intercalation of the photosensitizer between the π-stacked nucleobases, using classical mechanics approaches, and in the determination of the ground-state structures of the adducts, at the semiempirical − or ab initio single-reference RHF, DFT, MP2, and CCSD(T) levels . The complexes have been determined much more stable in the noncoplanar trans than in the stacked cis arrangements (see Figure ) .…”