Molecular dynamics simulations and their application to four-stranded DNA

Abstract

This review provides a critical assessment of the advantages and limitations of modeling methods available for guanine quadruplex (G-DNA) molecules. We characterize the relations of simulations to the experimental techniques and explain the actual meaning and significance of the results. The following aspects are discussed: pair-additive approximation of the empirical force fields, sampling limitations stemming from the simulation time and accuracy of description of base stacking, H-bonding, sugar-phosphate backbone and ions by force fields. Several methodological approaches complementing the classical explicit solvent molecular dynamics simulations are commented on, including enhanced sampling methods, continuum solvent methods, free energy calculations and gas phase simulations. The successes and pitfalls of recent simulation studies of G-DNA are demonstrated on selected results, including studies of cation interactions and dynamics of G-DNA stems, studies of base substitutions (inosine, thioguanine and mixed tetrads), analysis of possible kinetic intermediates in folding pathway of a G-DNA stem and analysis of loop regions of G-DNA molecules.

NMR spectroscopy of G-quadruplexes

“…So far, the dynamics of G-quadruplex nucleic acids has been mainly analyzed using simulation methods [187][188][189]. Investigations of G-quadruplex dynamics by NMR spectroscopy might give futher insights to understanding its folding pathway [190] and possibly motion-related molecular recognition.…”

Mass spectrometry and ion mobility spectrometry of G-quadruplexes. A study of solvent effects on dimer formation and structural transitions in the telomeric DNA sequence d(TAGGGTTAGGGT)

“…Oligodeoxynucleotides dT 6 and d(TAGGGT) 2 were purchased from Eurogentec (Belgium) and used without further purification. For all ESI-MS experiment, the sequence dT 6 (monoisotopic mass 1762.318 Da) was used as an internal standard for normalising peak intensities.…”

“…Nevertheless, several groups have shown, based on theory and experiments, that many structural elements of proteins and nucleic acids can be conserved in the gas phase sufficiently long to be probed before destruction (for a review, see reference [4]). Fortunately, G-quadruplexes are the nucleic acid structures that are the most prone to be preserved in the gas phase [5][6][7], thanks to the enhancement of hydrogen bonding (between guanines forming G-quartets) and electrostatic interactions (between the central cations and the G-quartet bases) in vacuo.…”

The Determination of Quadruplex Structures

“…This is a rapidly expanding area, and the problems of adequately dealing with the dominant long-range electrostatic interactions in quadruplexes (Smirnov & Shafer, 2007) have now been largely overcome (Strahan, Keniry & Shafer, 1998;Šponer & Špačková, 2007). The simple molecular mechanics force field is still almost universally used, with the formalism being that the energetics of a molecule (V) is described in terms of the sum of a number of factors: The AMBER force field has been extensively parameterized for nucleic acids (see Pérez et al, 2007 for a recent update of backbone parameters) and is the most commonly used one for quadruplex simulations, usually performed within the AMBER11 package (http://ambermd.org).…”