STRUCTURAL DIFFERENCES BETWEEN THE FREE AND BOUND-STATES OF THE DNA-BISINTERCALATING PEPTIDE YSPTSPSY

The YSPTSPSY peptide is a DNA-bisintercalator that can adopt nonrandom conformations in solution. Strategies based on random conformational search and energy minimizations have been applied to generate populati ons of conformers characterizing YSPTSPSY. Subsequent analysis based o n statistical methods and clustering allowed to determine the existenc e of four classes of conformers containing beta- and/or gamma-turns. N MR spectra of YSPTSPSY in solution provide evidence for such structure s. Employing a Monte Carlo-based docking procedure, the YSPTSPSY pepti de was docked in a DNA double-helical fragment with the sequence [d(GA CGTC)](2). The peptide binds on the minor groove of DNA stacking the c entral CG base pairs, in a manner similar to that observed in complexe s of triostin A with DNA. Upon binding, the structure of the C-termina l segment is modified into a type I beta-turn. Five intermolecular hyd rogen bonds are observed, but the van der Waals interactions constitut e the major stabilization factor for the complex. NMR chemical shifts, coupling constants, and NOESY connectivities are in agreement with th e molecular model.