Hairpins participating in folding of human telomeric sequence quadruplexes studied by standard and T-REMD simulations

Abstract

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 ∼130 μs of atomistic simulations. Antiparallel G-hairpins should spontaneously form in all stages of the folding to support lateral and diagonal loops, with sub-μs 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.

Folding of guanine quadruplex molecules–funnel-like mechanism or kinetic partitioning? An overview from MD simulation studies

“…While our paper was under review, two additional experimental studies appeared [22,23], which are fully consistent with the preceding MD data [24][25][26][27]. They revealed kinetic partitioning (i.e., multi-pathway, branched) model of GQ folding with dominant role played by well-structured four-stranded intermediates.…”

Folding and misfolding pathways of G-quadruplex DNA

“…The rate constants then suggest that intermediate 1a is structurally closer to the hybrid-2 than to the hybrid-1 structure. Molecular modeling shows that hairpins and G-triplexes are stable only when their strands are antiparallel (49,54). We therefore propose that for telomeric sequences, the 1a intermediate would have its 5′-end folded in an antiparallel manner.…”

“…Others have proposed branched mechanisms where both the unfolded species, an intermediate (triplex or other) and the G-quadruplex are in equilibrium, with (52) or without intermediates (38,53). Molecular dynamics simulations also suggest that the folding of the human telomeric sequences proceeds through a complex branched mechanism (49,54,55). …”

Reparameterizations of theχTorsion and Lennard-JonesσParameters Improve the Conformational Characteristics of Modified Uridines

“…Based on the results obtained in our previous study and with the reports on the current successes achieved through the development and reoptimization of the dihedral potentials and Lennard‐Jones parameters, specifically the glycosidic torsion potentials, we set specific objectives for this work. Our main objective was to reparameterize the glycosidic ( χ ) torsion parameters at the individual nucleoside level for 2SU, 4SU, and PSU.…”