PHYSICAL AND BIOLOGICAL PROPERTIES OF Z-DNA

已知DNA是具有多种构象的柔性聚合物 近年来，人们发现蛋白质与蛋白质之间的相互作用 DNA的Z型和A型， 构象之间的转换可能在 DNA功能的表达。 然而，由于替代DNA构象 很可能在基因组中少量存在，并且不稳定 在正常溶液条件下，需要使用综合模型 多核苷酸来研究DNA中的构象转变。 我们的实验室已经通过合成聚合物做了必要的基础工作， 在温和的条件下稳定存在于五种不同的特定 构象：低盐和高盐Z形式，规则和交替 A形式和交替的B形式。 尽管DNA的其他构象 可能存在于细胞中，如果替代DNA结构被 生理上重要的，上述结构中的至少一个将被 其中。 我建议进行几项互补的研究： 1)物理表征。 这将涉及调查 各种构象的相对稳定性， 环境参数（温度，特定离子结合，动力学， 等）; 2)化学表征。 将比较 各种构象对烷基化剂的反应性，以及 模型多核苷酸对嵌入药物的行为将是 探索; 3）生物学表征。 警方将进行搜查， 与非标准构象特异性结合的蛋白质。 此外，我们的实验室正在继续研究 B-Z跃迁的依赖性。 为了了解其结构特征 在稳定我们合成的Z型中很重要 序列，交替嘌呤-嘧啶聚合物和确定 序列和碱基组成对B-Z转变的影响。 内 在未来几年里，我们希望能够预测 任何给定的序列都将处于Z构象。

DNA is known to be a flexible polymer with a number of conformations available to it. In recent years proteins have been found which interact with the Z form and the A form of DNA, so that alternative conformations and transitions between conformations are likely to have a role in the expression of DNA function. However, since alternative DNA conformations are most likely present in small amounts in the genome and are unstable under normal solution conditions, it is necessary to use synthetic model polynucleotides to study conformational transitions in DNA. Our laboratory has done necessary groundwork by synthesizing polymers that exist stably under mild conditions in five different specific conformations: the low and high salt Z forms, the regular and alternating A forms, and the alternating B form. Although other conformations of DNA may exist in a cell, it seems likely that if alternative DNA structures are physiologically important, at least one of the above structures will be among them. I propose to pursue several complementary lines of research: 1) Physical characterization. This will involve investigation of the relative stability of the various conformations as a function of environmental parameters (temperature, specific ion binding, kinetics, etc.); 2) Chemical characterization. Comparison will be made of the reactivities of the various conformations toward alkylating agents, and the behavior of the model polynucleotides toward intercalating drugs will be explored; 3) Biological characterization. A search will be conducted for proteins which bind specifically to the non-standard conformations. Additionally, our laboratory is continuing work begun on the sequence dependence of the B-Z transition. To understand the structural features that are important in stabilizing the Z form we are synthesizing defined sequence, alternating purine- pyrimidine polymers and determining the effect of sequence and base composition on the B-Z transition. Within the next few years we expect to be able to predict the conditions under which any given sequence will be in the Z conformation.