期刊
NUCLEIC ACIDS RESEARCH
卷 43, 期 20, 页码 9626-9644出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv994
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资金
- Czech Science Foundation [P208/11/1822]
- project 'CEITEC-Central European Institute of Technology' [CZ.1.05/1.1.00/02.0068]
- Ministry of Education, Youth and Sports of the Czech Republic [LO1305]
- Student Project [Palacky University] [IGA_PrF_2015_027]
- European Organization for Molecular Biology [IG2535]
- Marie-Curie Re-integration (ECOPOD)
- European Research Council [S-RNA-S] [306662]
- Praemium Academiae
- European Research Council (ERC) [306662] Funding Source: European Research Council (ERC)
DNA G-hairpins are potential key structures participating in folding of human telomeric guanine quadruplexes (GQ). We examined their properties by standard MD simulations starting from the folded state and long T-REMD starting from the unfolded state, accumulating similar to 130 mu s of atomistic simulations. Antiparallel G-hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-mu s scale rearrangements between them. We found no clear predisposition for direct folding into specific GQ topologies with specific syn/anti patterns. Our key prediction stemming from the T-REMD is that an ideal unfolded ensemble of the full GQ sequence populates all 4096 syn/anti combinations of its four G-stretches. The simulations can propose idealized folding pathways but we explain that such few-state pathways may be misleading. In the context of the available experimental data, the simulations strongly suggest that the GQ folding could be best understood by the kinetic partitioning mechanism with a set of deep competing minima on the folding landscape, with only a small fraction of molecules directly folding to the native fold. The landscape should further include non-specific collapse processes where the molecules move via diffusion and consecutive random rare transitions, which could, e.g. structure the propeller loops.
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