Design of stapled DNA-minor-groove-binding molecules with a mutable atom simulated annealing method

J Comput Aided Mol Des. 1997 Nov;11(6):539-46. doi: 10.1023/a:1007985019866.

Abstract

We report the design of optimal linker geometries for the synthesis of stapled DNA-minor-groove-binding molecules. Netropsin, distamycin, and lexitropsins bind side-by-side to mixed-sequence DNA and offer an opportunity for the design of sequence-reading molecules. Stapled molecules, with two molecules covalently linked side-by-side, provide entropic gains and restrain the position of one molecule relative to its neighbor. Using a free-atom simulated annealing technique combined with a discrete mutable atom definition, optimal lengths and atomic composition for covalent linkages are determined, and a novel hydrogen bond 'zipper' is proposed to phase two molecules accurately side-by-side.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Binding Sites
  • DNA / chemistry*
  • DNA / ultrastructure
  • Distamycins / chemistry
  • Entropy
  • Hydrogen Bonding
  • Hydroxides
  • Netropsin / analogs & derivatives
  • Netropsin / chemistry*
  • Structure-Activity Relationship

Substances

  • Distamycins
  • Hydroxides
  • lexitropsin
  • Netropsin
  • stallimycin
  • DNA