DESIGN OF STAPLED DNA-MINOR-GROOVE-BINDING MOLECULES WITH A MUTABLE ATOM SIMULATED ANNEALING METHOD

We report the design of optimal linker geometries for the synthesis of stapled DNA-minor-groove-binding molecules. Netropsin, distamycin, an d lexitropsins bind side-by-side to mixed-sequence DNA and offer an op portunity for the design of sequence-reading molecules. Stapled molecu les, with two molecules covalently linked side-by-side, provide entrop ic gains and restrain the position of one molecule relative to its nei ghbor. Using a free-atom simulated annealing technique combined with a discrete mutable atom definition, optimal lengths and atomic composit ion for covalent linkages are determined, and a novel hydrogen bond 'z ipper' is proposed to phase two molecules accurately side-by-side.