This Article Full Text Full Text (PDF) Supplemental Material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stefl, R. Articles by Sponer, J. Search for Related Content PubMed PubMed Citation Articles by Stefl, R. Articles by Sponer, J.

Formation Pathways of a Guanine-Quadruplex DNA Revealed by Molecular Dynamics and Thermodynamic Analysis of the Substates

Richard tefl ^* , Thomas E. Cheatham, III , Nad'a paková , Eva Fadrná ^*, Imre Berger , Jaroslav Koa ^* and Jií poner 

^* National Center for Biomolecular Research, Masaryk University, 612 37 Brno, Czech Republic; Departments of Medicinal Chemistry and of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, 84112 USA; Institute of Biophysics, Academy of Sciences of the Czech Republic, and National Center for Biomolecular Research, 612 65 Brno, Czech Republic; and Institute for Molecular Biology and Biophysics, CH-8093 Zurich, Switzerland

Correspondence: Address reprint requests to Thomas E. Cheatham III, E-mail: tec3{at}utah.edu; or Jií poner, E-mail: sponer{at}ncbr.chemi.muni.cz.

The formation of a cation-stabilized guanine quadruplex (G-DNA) stem is an exceptionally slow process involving complex kinetics that has not yet been characterized at atomic resolution. Here, we investigate the formation of a parallel stranded G-DNA stem consisting of four strands of d(GGGG) using molecular dynamics simulations with explicit inclusion of counterions and solvent. Due to the limitations imposed by the nanosecond timescale of the simulations, rather than watching for the spontaneous formation of G-DNA, our approach probes the stability of possible supramolecular intermediates (including two-, three-, and four-stranded assemblies with out-of-register basepairing between guanines) on the formation pathway. The simulations suggest that "cross-like" two-stranded assemblies may serve as nucleation centers in the initial formation of parallel stranded G-DNA quadruplexes, proceeding through a series of rearrangements involving trapping of cations, association of additional strands, and progressive slippage of strands toward the full stem. To supplement the analysis, approximate free energies of the models are obtained with explicit consideration of the integral cations. The approach applied here serves as a prototype for qualitatively investigating other G-DNA molecules using molecular dynamics simulation and free-energy analysis.

This article has been cited by other articles:

				A. N. Lane, J. B. Chaires, R. D. Gray, and J. O. Trent Stability and kinetics of G-quadruplex structures Nucleic Acids Res., August 21, 2008; (2008) gkn517v1. [Abstract] [Full Text] [PDF]

				S. Haider, G. N. Parkinson, and S. Neidle Molecular Dynamics and Principal Components Analysis of Human Telomeric Quadruplex Multimers Biophys. J., July 1, 2008; 95(1): 296 - 311. [Abstract] [Full Text] [PDF]

				C. Bardin and J. L. Leroy The formation pathway of tetramolecular G-quadruplexes Nucleic Acids Res., February 2, 2008; 36(2): 477 - 488. [Abstract] [Full Text] [PDF]

				S. Burge, G. N. Parkinson, P. Hazel, A. K. Todd, and S. Neidle Quadruplex DNA: sequence, topology and structure Nucleic Acids Res., November 14, 2006; 34(19): 5402 - 5415. [Abstract] [Full Text] [PDF]

				P. Hazel, G. N Parkinson, and S. Neidle Predictive modelling of topology and loop variations in dimeric DNA quadruplex structures. Nucleic Acids Res., January 1, 2006; 34(7): 2117 - 2127. [Abstract] [Full Text] [PDF]

				F. Razga, J. Koca, J. Sponer, and N. B. Leontis Hinge-Like Motions in RNA Kink-Turns: The Role of the Second A-Minor Motif and Nominally Unpaired Bases Biophys. J., May 1, 2005; 88(5): 3466 - 3485. [Abstract] [Full Text] [PDF]

				J.-L. Mergny, A. De Cian, A. Ghelab, B. Saccà, and L. Lacroix Kinetics of tetramolecular quadruplexes Nucleic Acids Res., January 7, 2005; 33(1): 81 - 94. [Abstract] [Full Text] [PDF]

				P. Varnai and K. Zakrzewska DNA and its counterions: a molecular dynamics study Nucleic Acids Res., August 10, 2004; 32(14): 4269 - 4280. [Abstract] [Full Text] [PDF]

				E. Fadrna, N. Spackova, R. Stefl, J. Koca, T. E. Cheatham 3rd, and J. Sponer Molecular Dynamics Simulations of Guanine Quadruplex Loops: Advances and Force Field Limitations Biophys. J., July 1, 2004; 87(1): 227 - 242. [Abstract] [Full Text] [PDF]