Sequence-Structure Relationships and Information Readout in Double-Helical DNA

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Dr. Dickerson is using x-ray crystallography of synthetic DNA oligomers to learn how the base sequence influences local helix structure in a manner that can contribute to specific recognition of the DNA by restriction enzymes, repressors and other control proteins, and by antitumor drugs. Previous work by him and by others has shown that B-DNA is more sensitive to sequence perturbation than A-DNA, with Z-DNA least sensitive. Regions of B-DNA containing base pairs AT have a narrower and deeper minor groove than do GC or mixed-sequence regions, and provide better binding sites for planar polymeric antitumor drugs. Dr. Dickerson has shown that the narrow AT minor grooves contain an ordered, zig-zag spine of hydration with two waters per base pair, whereas wider general-sequence minor grooves have to ribbons of hydration down the walls of the grove, again with two waters per base pair. AT base pairs have greater propeller twist than GC, especially if a succession of A's in one strand permits major groove cross-strand H bonds. Dr. Dickerson intends to examine key base sequences in several crystal forms, to isolate the influence of crystal packing. The goal is to predict local helix deformations from base sequence, and learn how to design sites that will be recognized by specific drugs or proteins.