Folding pathways of hybrid-1 and hybrid-2 G-quadruplex structures

The G-rich sequence in the human telomeric DNA can form the G-quadruplex structure. The G-quadruplex structure has become an attractive target for the anticancer drugs, because it effectively inhibits telomerase activity. Recently, the human telomere G-quadruplex in K(+) solution has been determined as a hybrid structure. This structure is called hybrid-1. More recently, the hybrid-2 G-quadruplex has been determined by NMR. Hybrid-2 G-quadruplex differs from hybrid-1 in its loop arrangement and strand orientation. Here, we propose the folding pathways of hybrid-1 and hybrid-2 G-quadruplex structures. In hybrid-1, we proposed two pathways. In one pathway, the random coil forms triplex-1; in another pathway, the random coil forms chair-1. Similarly, we proposed two pathways in hybrid-2. In one pathway, the random coil forms triplex-2; in another pathway, the random coil forms chair-2. The folding pathways of human telomeric hybrid-1 G-quadruplex and hybrid-2 G-quadruplex structures were proposed using MO calculation and molecular modelling.