SEQUENCE SPECIFIC RECOGNITION OF DNA

双螺旋DNA的序列特异性识别是一个重要的研究领域。 调节细胞功能的生物过程 包括转录、复制和细胞分裂。 的能力 设计合成分子，将序列特异性地结合到独特的位点 对治疗遗传性、致癌性、 和病毒性疾病。 结构-功能问题的基础研究，如 将进行DNA的识别和共价修饰。 研究 将集中在识别的小沟双螺旋DNA的一个 新的2：1肽：DNA基序。 未来四年的具体目标 年是：（1）发展固相法合成 含有咪唑和N-甲基吡咯甲酰胺的寡肽。 （二） 定义识别2：1肽的序列组成规则 DNA模体的构建及26个分子的能量学研究 不同的发夹肽。 (3)定义结合位点的上限 2：1的主题。 (4)设计和研究结合的能量学 一类新的α-氨基酸连接的咪唑-甲基吡咯甲酰胺 缩氨酸 (5)一类刚性发夹肽合成与分析 亲和力和特异性的能量学。 (6)合成一类 环肽，并分析亲和性和特异性的能量学。 (7)开发了一种通过2：1 DNA进行序列特异性DNA弯曲的方法 母题 (8)发展双螺旋DNA的序列特异性连接 由小沟结合肽促进。 除了合成， 特异性和加州理工学院的精力充沛的研究，所有新的合成肽 将被送往加州大学伯克利分校进行肽-DNA的结构解析 通过2-D NMR测定配合物。

The sequence specific recognition of double helical DNA is an essential biological process responsible for the regulation of cellular functions including transcription, replication, and cell division. The ability to design synthetic molecules that bind sequence specifically to unique sites on human DNA has major implications for the treatment of genetic, oncogenic and viral diseases. Basic research on structure-function issues such as recognition and covalent modification of DNA will be carried out. Research will focus on recognition of the minor groove of double helical DNA by a novel 2:1 peptide:DNA motif. Our specific objectives during the next four years are: (1) develop solid phase methods for the synthesis of oligopeptides containing imidazole and N-methylpyrrolecarboxamides. (2) define the sequence composition rules for recognition for the 2:1 peptide DNA motif by constructing and studying of the energetics of twenty-six different hairpin peptides. (3) define the upper limits for binding site size by the 2:1 motif. (4) design and study the energetics of binding of a novel class of alpha-amino acid linked imidazole-methylpyrrolecarboxamide peptides. (5) synthesize a class of rigid hairpin peptides and analyze the energetics for affinity and specificity. (6) synthesize a class of cyclic peptides and analyze the energetics for affinity and specificity. (7) develop a method for sequence specific DNA bending by the 2:1 DNA motif. (8) develop sequence specific ligation of double helical DNA promoted by minor groove binding prptides. In addition to the synthesis, specificity, and energetic studies at Caltech, all new synthetic peptides will be sent to UC Berkeley for structure elucidation of the peptide-DNA complexes by 2-D NMR.