A combined QM and MM investigation into guanine quadruplexes

Abstract: This paper reports on the application of quantum mechanical (QM) energy calculations, QM optimisations and MD simulations to explore the stability of a human telomeric guanine quadruplex, containing potassium and sodium cations. G-quadruplexes are of great biological interest as it has been suggested that they offer a novel path to cancer inhibition. By understanding the stability and geometry of these DNA features gives us the ability to design ligands which can bind and stabilise the G-quadruplex. There are significant structural differences between the potassium containing crystal structure of human telomeric G-quadruplex and the sodium containing NMR structure; in this paper, we investigate the energetics and dynamics of the potassium derived crystal structure and a model for the sodium containing structure. QM investigations upon the 12 G-quadruplex core, extracted from the human potassium quadruplex crystal structure, indicate that replacement of the potassium cations with sodium yields an energetically more favourable structure. However, attempts to geometry optimise both structures at the QM level proved unsuccessful, the structure of the partially optimised potassium containing G-quadruplex retains significant structural integrity with respect to the original crystal structure, whilst the sodium containing G-quadruplex shows significant structural distortion. QM investigation of the 12 G-quadruplex core containing no cations unsurprisingly yields a highly unfavourable energetic structure. MD simulations on the complete quadruplex structure, containing potassium cations, yields a remarkably stable structure after 4ns of simulation, the most significant deviation from the original crystal structure being the loss of the capping potassium cation from the structure. MD simulation of the sodium containing quadruplex for 4ns show significant structural reorganisation compared with the original potassium containing crystal structure. [Copyright &y& Elsevier]