A comparison of four different conformations adopted by human telomeric G-quadruplex using computer simulations

The telomeric G-quadruplexes for their unique structural features are considered as potential anticancer drug targets. These, however, exhibit structural polymorphism as different topology types for the intra-molecular G-quadruplexes from human telomeric G-rich sequences have been reported based on NMR spectroscopy and X-ray crystallography. These techniques provide detailed atomic-level information about the molecule but relative conformational stability of the different topologies remains unsolved. Therefore, to understand the conformational preference, we have carried out quantum chemical calculations on G-quartets; used all-atom molecular dynamics (MD) simulations and steered molecular dynamics (SMD) simulations to characterize the four human telomeric G-quadruplex topologies based on its G-tetrad core-types, viz., parallel, anti-parallel, mixed-(3 + 1)-form1 and mixed-(3 + 1)-form2. We have also studied a non-telomeric sequence along with these telomeric forms giving a comparison between the two G-rich forms. The structural properties such as base pairing, stacking geometry and backbone conformations have been analyzed. The quantum calculations indicate that presence of a sodium ion inside the G-tetrad plane or two potassium ions on both sides of the plane give it an overall planarity which is much needed for good stacking to form a helix. MD simulations indicate that capping of the G-tetrad core by the TTA loops keep the terminal guanine bases away from water. The SMD simulations along with equilibrium MD studies indicate that the parallel and non-telomeric forms are comparatively less stable. We could come to the conclusion that the anti-parallel form and also the mixed-(3 + 1)-form1 topology are most likely to represent the major conformation., 2016. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 83-99, 2016.