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

Barira Islam, Petr Stadlbauer, Alejandro Gil-Ley, Guillermo Pérez-Hernández, Shozeb Haider, Stephen Neidle, Giovanni Bussi, Pavel Banas, Michal Otyepka, Jiri Sponer

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We have carried out a series of extended unbiased molecular dynamics (MD) simulations (up to 10 μs long, â?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 Trans state of the first propeller loop nucleotide could be related to the indispensable bsc0 α/ 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.

Original languageEnglish
Pages (from-to)2458-2480
Number of pages23
JournalJournal of Chemical Theory and Computation
Volume13
Issue number6
Early online date5 May 2017
DOIs
Publication statusPublished - 13 Jun 2017
Externally publishedYes

Fingerprint

propellers
Propellers
DNA
deoxyribonucleic acid
Conformations
field theory (physics)
Tempering
simulation
tempering
Topology
replicas
Nucleotides
topology
Molecular dynamics
nucleotides
Sampling
Computer simulation
sampling
molecular dynamics

Cite this

Islam, Barira ; Stadlbauer, Petr ; Gil-Ley, Alejandro ; Pérez-Hernández, Guillermo ; Haider, Shozeb ; Neidle, Stephen ; Bussi, Giovanni ; Banas, Pavel ; Otyepka, Michal ; Sponer, Jiri. / Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations. In: Journal of Chemical Theory and Computation. 2017 ; Vol. 13, No. 6. pp. 2458-2480.
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Islam, B, Stadlbauer, P, Gil-Ley, A, Pérez-Hernández, G, Haider, S, Neidle, S, Bussi, G, Banas, P, Otyepka, M & Sponer, J 2017, 'Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations', Journal of Chemical Theory and Computation, vol. 13, no. 6, pp. 2458-2480. https://doi.org/10.1021/acs.jctc.7b00226

Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations. / Islam, Barira; Stadlbauer, Petr; Gil-Ley, Alejandro; Pérez-Hernández, Guillermo; Haider, Shozeb; Neidle, Stephen; Bussi, Giovanni; Banas, Pavel; Otyepka, Michal; Sponer, Jiri.

In: Journal of Chemical Theory and Computation, Vol. 13, No. 6, 13.06.2017, p. 2458-2480.

Research output: Contribution to journalArticle

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T1 - Exploring the Dynamics of Propeller Loops in Human Telomeric DNA Quadruplexes Using Atomistic Simulations

AU - Islam, Barira

AU - Stadlbauer, Petr

AU - Gil-Ley, Alejandro

AU - Pérez-Hernández, Guillermo

AU - Haider, Shozeb

AU - Neidle, Stephen

AU - Bussi, Giovanni

AU - Banas, Pavel

AU - Otyepka, Michal

AU - Sponer, Jiri

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N2 - We have carried out a series of extended unbiased molecular dynamics (MD) simulations (up to 10 μs long, â?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 Trans state of the first propeller loop nucleotide could be related to the indispensable bsc0 α/ 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.

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DO - 10.1021/acs.jctc.7b00226

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SN - 1549-9618

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