Structural dynamics of possible late-stage intermediates in folding of quadruplex DNA studied by molecular simulations

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Authors	STADLBAUER Petr KREPL Miroslav CHEATHAM Thomas E. KOČA Jaroslav ŠPONER Jiří
Year of publication	2013
Type	Article in Periodical
Magazine / Source	Nucleic Acids Research
MU Faculty or unit	Central European Institute of Technology
Citation
Web	http://nar.oxfordjournals.org/content/41/14/7128
Doi	http://dx.doi.org/10.1093/nar/gkt412
Field	Physical chemistry and theoretical chemistry
Keywords	HUMAN TELOMERIC DNA; TETRAMOLECULAR G-QUADRUPLEXES; PARTICLE MESH EWALD; AMBER FORCE-FIELD; NUCLEIC-ACIDS; CRYSTAL-STRUCTURE; BIOMOLECULAR SIMULATIONS; INTERACTION POTENTIALS; FORMATION PATHWAYS; SOLUTION INSIGHTS
Attached files	stadlbauer_nar_2013.pdf
Description	Explicit solvent molecular dynamics simulations have been used to complement preceding experimental and computational studies of folding of guanine quadruplexes (G-DNA). We initiate early stages of unfolding of several G-DNAs by simulating them under no-salt conditions and then try to fold them back using standard excess salt simulations. There is a significant difference between G-DNAs with all-anti parallel stranded stems and those with stems containing mixtures of syn and anti guanosines. The most natural rearrangement for all-anti stems is a vertical mutual slippage of the strands. This leads to stems with reduced numbers of tetrads during unfolding and a reduction of strand slippage during refolding. The presence of syn nucleotides prevents mutual strand slippage; therefore, the antiparallel and hybrid quadruplexes initiate unfolding via separation of the individual strands. The simulations confirm the capability of G-DNA molecules to adopt numerous stable locally and globally misfolded structures. The key point for a proper individual folding attempt appears to be correct prior distribution of syn and anti nucleotides in all four G-strands. The results suggest that at the level of individual molecules, G-DNA folding is an extremely multi-pathway process that is slowed by numerous misfolding arrangements stabilized on highly variable timescales.
Related projects:	CEITEC - Central European Institute of Technology