Coarse-Grained Simulations Complemented by Atomistic Molecular Dynamics Provide New Insights into Folding and Unfolding of Human Telomeric G-Quadruplexes

STADLBAUER, Petr, L MAZZANTI, T CRAGNOLINI, DJ WALES, P DERREUMAUX, S PASQUALI a Jiří ŠPONER. Coarse-Grained Simulations Complemented by Atomistic Molecular Dynamics Provide New Insights into Folding and Unfolding of Human Telomeric G-Quadruplexes. Journal of Chemical Theory and Computation. Washington DC: American Chemical Society, 2016, roč. 12, č. 12, s. 6077-6097. ISSN 1549-9618. Dostupné z: https://dx.doi.org/10.1021/acs.jctc.6b00667.

Základní údaje

• Originální název: Coarse-Grained Simulations Complemented by Atomistic Molecular Dynamics Provide New Insights into Folding and Unfolding of Human Telomeric G-Quadruplexes
• Autoři: STADLBAUER, Petr, L MAZZANTI, T CRAGNOLINI, DJ WALES, P DERREUMAUX, S PASQUALI a Jiří ŠPONER.
• Vydání: Journal of Chemical Theory and Computation, Washington DC, American Chemical Society, 2016, 1549-9618.

Další údaje

• Originální jazyk: angličtina
• Typ výsledku: Článek v odborném periodiku
• Utajení: není předmětem státního či obchodního tajemství
• WWW: URL
• Impakt faktor: Impact factor: 5.245
• Doi: http://dx.doi.org/10.1021/acs.jctc.6b00667
• UT WoS: 000389866500034
• Příznaky: Mezinárodní význam, Recenzováno

Anotace

G-quadruplexes are the most important non canonical DNA architectures. Many quadruplex-forming sequences, including the human telomeric sequence d(GGGTTA)(n), have been investigated due to their implications in cancer and other diseases, and because of their potential in DNA-based nanotechnology. Despite the availability of atomistic structural studies of folded G-quadruplexes, their folding pathways remain mysterious, and mutually contradictory models of folding coexist in the literature. Recent experiments convincingly demonstrated that G-quadruplex folding often takes days to reach thermodynamic equilibrium. Based on atomistic simulations of diverse classes of intermediates in G-quadruplex folding, we have suggested that the folding is an extremely multipathway process combining a kinetic partitioning mechanism with conformational diffusion. However, complete G-quadruplex folding is far beyond the time scale of atomistic simulations. Here we use high-resolution coarse-grained simulations to investigate potential unfolding intermediates, whose structural dynamics are then further explored with all-atom simulations. This multiscale approach indicates how various pathways are interconnected in a complex network. Spontaneous conversions between different folds are observed. We demonstrate the inability of simple order parameters, such as radius of gyration or the number of native H-bonds, to describe the folding landscape of the G-quadruplexes. Our study also provides information relevant to further development of the coarse grained force field.