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

Dickerson博士正在使用合成DNA低聚物的x射线晶体学来了解碱基序列如何影响局部螺旋结构，从而有助于限制性内切酶、抑制物和其他控制蛋白以及抗肿瘤药物对DNA的特定识别。他和其他人之前的工作表明，B-DNA对序列扰动比A-DNA更敏感，Z-DNA最不敏感。含有AT碱基对的B-DNA区域比GC或混合序列区域具有更窄更深的小凹槽，为平面聚合抗肿瘤药物提供了更好的结合位点。迪克森博士已经证明，狭窄的AT小凹槽包含一个有序的、锯齿状的水合作用脊，每对碱基对有两个水，而更宽的一般序列小凹槽必须有水合作用带沿着小凹槽的壁，每对碱基对也有两个水。AT碱基对比GC具有更大的螺旋桨扭，特别是当一条链上的a序列允许主要槽型交叉链氢键时。迪克森博士打算检查几种晶体形式的关键碱基序列，以分离晶体堆积的影响。目标是从碱基序列中预测局部螺旋变形，并学习如何设计将被特定药物或蛋白质识别的位点。

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.