Structural Dynamics of Lateral and Diagonal Loops of Human Telomeric G-Quadruplexes in Extended MD Simulations

Abstract

The NMR solution structures of human telomeric (Htel) G-quadruplexes (GQs) are characterized by the presence of two lateral loops complemented by either diagonal or propeller loops. Bases of a given loop can establish interactions within the loop as well as with other loops and the flanking bases. This can lead to a formation of base alignments above and below the GQ stems. These base alignments are known to affect the loop structures and relative stabilities of different Htel GQ folds. We have carried out a total of 217 μs of classical (unbiased) molecular dynamics (MD) simulations starting from the available solution structures of Htel GQs to characterize structural dynamics of the lateral and diagonal loops, using several recent AMBER DNA force-field variants. As the loops are involved in diverse stacking and H-bonding interactions, their dynamics is slow, and extended sampling is required to capture different conformations. Nevertheless, although the simulations are far from being quantitatively converged, the data suggest that multiple 10 μs-scale simulations can provide a quite good assessment of the loop conformational space as described by the force field. The simulations indicate that the lateral loops may sample multiple coexisting conformations, which should be considered when comparing simulations with the NMR models as the latter include ensemble averaging. The adenine-thymine Watson-Crick arrangement was the most stable base pairing in the simulations. Adenine-adenine and thymine-thymine base pairs were also sampled but were less stable. The data suggest that the description of lateral and diagonal GQ loops in contemporary MD simulations is considerably more realistic than the description of propeller loops, though definitely not flawless.

Studying the excited electronic states of guanine rich DNA quadruples by quantum mechanical methods: main achievements and perspectives

“…On the other hand, additional investigations are necessary to shed light on the effect of the above reactions on the structural behaviour of G4, since the final outcome of these radical reactions is not clear. In this respect, MD simulations, already successfully employed to study the conformational dynamics of G4s, [82][83][84][85] surely could be usefully applied to ionized G4s.…”

Stability of Two-quartet G-quadruplexes and Their Dimers in Atomistic Simulations

“…29 In the present case we observe perturbation of GQ core of an experimentally determined structure, which is exceptionally rare in AMBER GQ simulations. [68][69][70][71][72]…”

“…As for the simulations of the complete 2N3M structure, Na + ions were more dynamic than K + ( Figure S4). 29,[68][69][70]73 In the Simulation 3a, three Na + ion exchange events were observed from 440 ns -2.28 μ s ( Figure S4a). These ion exchanges were linked to the entry of cation from the bottom quartet concurrent with a concerted movement leading to the escape of ion from the top quartet.…”

“…In contrast, any larger perturbation of the quartets in simulations of GQ structures derived from experiments indicate that an inadequate force field has been used. 42,97 Still, even with appropriate force fields, subtle details of the structures (details of quartet's H-bonds, 29,72 cation distribution, 29 backbone substates 57 and loop conformations 68,69,71 ) may be sampled imperfectly.…”

“…68 The description of lateral and diagonal loops appears to be more realistic. 69 iv) With commonly used force-field parameters, the pair additive force field underestimates the strength of the O6-cation interaction and thus also direct cation binding to the G-quartets. 71,102 In addition, when using monovalent cations that have parameters optimized to reproduce solvation energies with current water models, the cations inside the G-stem channel appear as too large (having a too large radius or too steep onset of the van der Waals repulsion).…”