Molecular Dynamics and Principal Components Analysis of Human Telomeric Quadruplex Multimers

¹ School of Pharmacy
² School of Pharmacy, Univ of London

^* To whom correspondence should be addressed. E-mail: stephen.neidle{at}pharmacy.ac.uk.

Submitted on August 24, 2007
Revised on September 27, 2007
Accepted on 3 March 2008

	Abstract

Guanine-rich DNA repeat sequences located at the terminal ends of chromosomal DNA can fold in a sequence-dependent manner into G-quadruplex structures, notably the terminal 150-200 nucleotides at the 3'end, which occur as a single-stranded DNA overhang. The crystal structures of quadruplexes with two and four human telomeric repeats show an all-parallel-stranded topology that is readily capable of forming extended stacks of such quadruplex structures, with external TTA loops positioned to potentially interact with other macromolecules. This paper reports on possible arrangements for these quadruplex dimers and tetramers, which can be formed from eight or sixteen telomeric DNA repeats, and on a methodology for modelling their interactions with small molecules. A series of computational methods including molecular dynamics, free energy calculations and principal components analysis, have been employed in order to characterise the properties of these higher-order G-quadruplex dimers and tetramers, with parallel-stranded topology. The results confirm the stability of the central G-tetrads, of the individual quadruplexes and of the resulting multimers. Principal components analysis has been carried out in order to highlight the dominant motions in these G-quadruplex dimer and multimer structures. The TTA loop is the most flexible part of the model and the overall multimer quadruplex becoming more stable with the addition of further G-tetrads. The addition of a ligand to the model confirms the hypothesis that flat planar chromophores stabilise G-quadruplex structures by making them less flexible.

Key Words: G-quadruplex, simulation, telomere