Structural stability analysis of the intermediates in the folding pathway of human telomeric hybrid-1 G-quadruplex based on fragment molecular orbital method

The human telomeric DNA sequence d[AGGG(TTAGGG)(3)] has been found to form different type of G-quadruplex structure based on NMR(1), X-ray crystallography(2) and circular dichroism (CD). Recently human telomeric hybrid-1 G-quadruplex structure in K(+) solution has been revealed by CD and NMR(3,4,5). However, folding pathway of G-quadruplex structures is not clear to date. It is important to elucidate the intermediate structure of human telomeric hybrid-1 G-quadruplex for drug discovery in addition to having essential knowledge of telomere. In this study, we designed two types of triplex intermediate model from hybrid-1 NMR structure and evaluated their stabilities with ab initio Fragment Molecular Orbital (FMO) method(6,7,8). The folding pathways of human telomeric hybrid-1 G-quadruplex structure are discussed.