0471940 - BFÚ 2017 RIV US eng J - Článek v odborném periodiku
Stadlbauer, Petr - Mazzanti, L. - Cragnolini, T. - Wales, D.J. - Derreumaux, P. - Pasquali, C. - Šponer, Jiří
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. Roč. 12, č. 12 (2016), s. 6077-6097. ISSN 1549-9618. E-ISSN 1549-9626
Grant CEP: GA ČR(CZ) GA16-13721S
Institucionální podpora: RVO:68081707
Klíčová slova: particle mesh ewald * amber force-field * free-energy profiles * binding dna aptamer
Kód oboru RIV: BO - Biofyzika
Impakt faktor: 5.245, rok: 2016 ; AIS: 1.969, rok: 2016
DOI: https://doi.org/10.1021/acs.jctc.6b00667

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.
Trvalý link: http://hdl.handle.net/11104/0269302