title: Conformational dynamics of the human propeller telomeric DNA quadruplex on a microsecond time scale.
abstract: The human telomeric DNA sequence with four repeats can fold into a parallel-stranded propeller-type topology. NMR structures solved under molecular crowding experiments correlate with the crystal structures found with crystal-packing interactions that are effectively equivalent to molecular crowding. This topology has been used for rationalization of ligand design and occurs experimentally in a number of complexes with a diversity of ligands, at least in the crystalline state. Although G-quartet stems have been well characterized, the interactions of the TTA loop with the G-quartets are much less defined. To better understand the conformational variability and structural dynamics of the propeller-type topology, we performed molecular dynamics simulations in explicit solvent up to 1.5 μs. The analysis provides a detailed atomistic account of the dynamic nature of the TTA loops highlighting their interactions with the G-quartets including formation of an A:A base pair, triad, pentad and hexad. The results present a threshold in quadruplex simulations, with regards to understanding the flexible nature of the sugar-phosphate backbone in formation of unusual architecture within the topology. Furthermore, this study stresses the importance of simulation time in sampling conformational space for this topology.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast BT9 7BL, UK.
authors.forename: Barira
authors.initials: B
authors.lastname: Islam
authors.forename: Miriam
authors.initials: M
authors.lastname: Sgobba
authors.forename: Charlie
authors.initials: C
authors.lastname: Laughton
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.forename: Jiri
authors.initials: J
authors.lastname: Sponer
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Shozeb
authors.initials: S
authors.lastname: Haider
mesh_terms: D016000:Cluster Analysis; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000737:chemistry; D016615:Telomere / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D014867:Water; D004247:DNA; D011188:Potassium