Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations

Abstract

We have carried out a series of extended unbiased molecular dynamics (MD) simulations (up to 10 μs long, ∼162 μs in total) complemented by replica-exchange with the collective variable tempering (RECT) approach for several human telomeric DNA G-quadruplex (GQ) topologies with TTA propeller loops. We used different AMBER DNA force-field variants and also processed simulations by Markov State Model (MSM) analysis. The slow conformational transitions in the propeller loops took place on a scale of a few μs, emphasizing the need for long simulations in studies of GQ dynamics. The propeller loops sampled similar ensembles for all GQ topologies and for all force-field dihedral-potential variants. The outcomes of standard and RECT simulations were consistent and captured similar spectrum of loop conformations. However, the most common crystallographic loop conformation was very unstable with all force-field versions. Although the loss of canonical γ-trans state of the first propeller loop nucleotide could be related to the indispensable bsc0 α/γ dihedral potential, even supporting this particular dihedral by a bias was insufficient to populate the experimentally dominant loop conformation. In conclusion, while our simulations were capable of providing a reasonable albeit not converged sampling of the TTA propeller loop conformational space, the force-field description still remained far from satisfactory.

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.…”

Computational Methods to Study G-Quadruplex–Ligand Complexes

“…78 A subsequent report by Sponer group to study loop conformations in parallel-stranded quadruplexes highlighted the limitations of these force fields to accurately reproduce experimental structure in all these force field versions. 81 However, it is worth mentioning that modifications of the AMBER force field to bsc0, bsc1 and OL15 were developed to improve the accuracy of simulating double-stranded DNA. 74 In spite of their limitations, these force fields have helped in improving the reliability to simulate quadruplexes.…”

“…Long timescale MD simulations of quadruplexes have shown that quadruplexes are transitionally stabilised on a shorter timescales and are far from equilibrium states. 76,81 A fully converged system requires extended sampling of the quadruplex-ligand systems. 76,81 A good example is the MD simulation used to study the interactions of tetra-substituted naphthalene diimide compound MM41 and quadruplexes formed in the gene promoter sequences, employing parmbsc0 force field supplemented with χ OL4 modifications.…”

“…76,81 A fully converged system requires extended sampling of the quadruplex-ligand systems. 76,81 A good example is the MD simulation used to study the interactions of tetra-substituted naphthalene diimide compound MM41 and quadruplexes formed in the gene promoter sequences, employing parmbsc0 force field supplemented with χ OL4 modifications. 36 The results from the MD simulations were able to demonstrate the favourable binding mode of MM41 to the BCL-2 quadruplexes.…”