Dominick Pamela K, Jarstfer Michael B
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, 27599-7360, USA.
J Am Chem Soc. 2004 Apr 28;126(16):5050-1. doi: 10.1021/ja039192z.
Guanine-rich DNA and RNA sequences can fold into unique structures known as G-quadruplexes. The structures of G-quadruplexes can be divided into several classes, depending on the parallel or antiparallel nature of the strands and the number of G-rich tracts present in an oligonucleotide. Oligonucleotides with single tracts of guanines form intermolecular parallel tetrameric G-quadruplexes. Oligonucleotides with two tracts of guanosines separated by two or more bases can form both intermolecular antiparallel fold-back dimeric and parallel tetrameric G-quadruplexes, and those with four tracts of guanosines can form both intramolecular parallel and antiparallel structures. Intramolecular G-qaudruplexes can fold into several folding topologies including antiparallel crossover basket, antiparallel chair, and parallel propeller. The ability to control the folding of G-quadruplexes would allow the physical, biochemical, and biological properties of these various folding topologies to be studied. Previously, the known methods to control the folding topology of G-quadruplexes included changing the buffer by varying the mono- and divalent cations that are present, and by changing the DNA sequence. Because the glycosidic bonds in the G-quartets of G-quadruplexes with parallel strands are in the anti conformation, we reasoned that incorporation of nucleoside analogues that prefer the anti conformation of the glycosidic bond into G-rich sequences would increase the preference for parallel G-quadruplex formation. As predicted, by positioning the conformationally constrained nucleotide analogue 2'-O-4'-C-methylene-linked ribonucleotide into specific positions of a DNA G-quadruplex we were able to shift the thermodynamically favored structure of a G-quadruplex from an antiparallel to a parallel structure.
富含鸟嘌呤的DNA和RNA序列可折叠成称为G-四链体的独特结构。根据链的平行或反平行性质以及寡核苷酸中存在的富含G的片段数量，G-四链体的结构可分为几类。具有单链鸟嘌呤的寡核苷酸形成分子间平行四聚体G-四链体。具有由两个或更多个碱基隔开的两个鸟苷链的寡核苷酸可以形成分子间反平行回折二聚体和平行四聚体G-四链体，而具有四个鸟苷链的寡核苷酸可以形成分子内平行和反平行结构。分子内G-四链体可以折叠成几种折叠拓扑结构，包括反平行交叉篮状、反平行椅状和平行螺旋桨状。控制G-四链体折叠的能力将使研究这些各种折叠拓扑结构的物理、生化和生物学特性成为可能。以前，控制G-四链体折叠拓扑结构的已知方法包括通过改变存在的单价和二价阳离子来改变缓冲液，以及改变DNA序列。由于具有平行链的G-四链体的G-四重体中的糖苷键处于反式构象，我们推断将更喜欢糖苷键反式构象的核苷类似物掺入富含G的序列中将增加形成平行G-四链体的偏好。正如所预测的，通过将构象受限的核苷酸类似物2'-O-4'-C-亚甲基连接的核糖核苷酸定位到DNA G-四链体的特定位置，我们能够将G-四链体的热力学有利结构从反平行结构转变为平行结构。
