Biophys J, September 1999, p. 1191-1205, Vol. 77, No. 3

NEW AND NOTABLE
Modeling Helix-Turn-Helix Protein-Induced DNA Bending with Knowledge-Based Distance Restraints

Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC

A crucial element of many gene functions is protein-induced DNA bending. Computer-generated models of such bending have generally been derived by using a presumed bending angle for DNA. Here we describe a knowledge-based docking strategy for modeling the structure of bent DNA recognized by a major groove-inserting -helix of proteins with a helix-turn-helix (HTH) motif. The method encompasses a series of molecular mechanics and dynamics simulations and incorporates two experimentally derived distance restraints: one between the recognition helix and DNA, the other between respective sites of protein and DNA involved in chemical modification-enabled nuclease scissions. During simulation, a DNA initially placed at a distance was "steered" by these restraints to dock with the binding protein and bends. Three prototype systems of dimerized HTH DNA binding were examined: the catabolite gene activator protein (CAP), the phage 434 repressor (Rep), and the factor for inversion stimulation (Fis). For CAP-DNA and Rep-DNA, the root mean square differences between model and x-ray structures in nonhydrogen atoms of the DNA core domain were 2.5 Å and 1.6 Å, respectively. An experimental structure of Fis-DNA is not yet available, but the predicted asymmetrical bending and the bending angle agree with results from a recent biochemical analysis.

Biophys J, September 1999, p. 1191-1205, Vol. 77, No. 3
© 1999 by the Biophysical Society   0006-3495/99/09/1191/15  $2.00

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