Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
25038568
DOI
10.1016/j.biochi.2014.07.009
PII: S0300-9084(14)00187-4
Knihovny.cz E-zdroje
- Klíčová slova
- G-DNA folding, Molecular dynamics, Quadruplex, Telomere, Triplex,
- MeSH
- DNA chemie MeSH
- G-kvadruplexy * MeSH
- konformace nukleové kyseliny * MeSH
- lidé MeSH
- nukleové kyseliny chemie genetika MeSH
- sekvence nukleotidů MeSH
- simulace molekulární dynamiky MeSH
- telomery chemie genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA MeSH
- nukleové kyseliny MeSH
We have carried out extended set of μs-scale explicit solvent MD simulations of all possible G-triplexes which can participate in folding pathways of the human telomeric quadruplex. Our study accumulates almost 60 μs of simulation data, which is by about three orders of magnitude larger sampling compared to the earlier simulations of human telomeric G-DNA triplexes. Starting structures were obtained from experimental quadruplex structures by deleting either the first or the last strand. The life-times of antiparallel triplexes with lateral and diagonal loops are at least on μs-scale, which should be sufficient to contribute to the folding pathways. However, the triplex states may involve structures with various local deviations from the ideal triplexes, such as strand tilting and various alternative and incomplete triads. The simulations reveal easy rearrangements between lateral and diagonal loop triplex topologies. Propeller loops of antiparallel triplexes may to certain extent interfere with the G-triplexes but these structures are still viable candidates to participate in the folding. In contrast, all-parallel all-anti triplexes are very unstable and are unlikely to contribute to the folding. Although our simulations demonstrate that antiparallel G-triplexes, if folded, would have life-times sufficient to participate in the quadruplex folding, the results do not rule out the possibility that the G-triplexes are out-competed by other structures not included in our study. Among them, numerous possible misfolded structures containing guanine quartets can act as off-path intermediates with longer life-times than the triplexes. Besides analyzing the structural dynamics of a diverse set of G-DNA triplexes, we also provide a brief discussion of the limitations of the simulation methodology, which is necessary for proper understanding of the simulation data.
Department of Medicinal Chemistry College of Pharmacy University of Utah Salt Lake City UT 84124 USA
Citace poskytuje Crossref.org
Computer Folding of Parallel DNA G-Quadruplex: Hitchhiker's Guide to the Conformational Space
Complexity of Guanine Quadruplex Unfolding Pathways Revealed by Atomistic Pulling Simulations
Structural dynamics of propeller loop: towards folding of RNA G-quadruplex
Extended molecular dynamics of a c-kit promoter quadruplex
