Structural Dynamics of Human Telomeric G-Quadruplex Loops Studied by Molecular Dynamics Simulations

Abstract

Loops which are linkers connecting G-strands and supporting the G-tetrad core in G-quadruplex are important for biological roles of G-quadruplexes. TTA loop is a common sequence which mainly resides in human telomeric DNA (hTel) G-quadruplex. A series of molecular dynamics (MD) simulations were carried out to investigate the structural dynamics of TTA loops. We found that (1) the TA base pair formed in TTA loops are very stable, the occupied of all hydrogen bonds are more than 0.95. (2) The TA base pair makes the adjacent G-quartet more stable than others. (3) For the edgewise loop and the diagonal loop, most loop bases are stacking with others, only few bases have considerable freedom. (4) The stabilities of these stacking structures are distinct. Part of the loops, especially TA base pairs, and bases stacking with the G-quartet, maintain certain stable conformations in the simulation, but other parts, like TT and TA stacking structures, are not stable enough. For the first time, spontaneous conformational switches of TTA edgewise loops were observed in our long time MD simulations. (5) For double chain reversal loop, it is really hard to maintain a stable conformation in the long time simulation under present force fields (parm99 and parmbsc0), as it has multiple conformations with similar free energies.

Characterization of potassium binding with human telomeres

“…In MD simulation, parmbsc0 combined FF99SB force field within AMBER12 software was applied, which has been validated for G-quadruplex structures by many nanoseconds state-of-theart molecular dynamics simulations. [24][25][26][27] The system was firstly energy minimized by the steepest descent method for 5000 steps with the AMBER sander module, during which K + and waters were free to move while G-quadruplex was restricted by a harmonic constraint of 100 kcal/mol per A. A following conjugate gradient minimization was then conducted for 5000 steps with no constraint on any component.…”

The effects of monovalent metal ions on the conformation of human telomere DNA using analytical ultracentrifugation

“…[1][2][3][4][5][6][7][8][9][10][11] Human telomeres containing tandem repeats of sequence d(TTAGGG) at their extreme 3 0 -end are the complexes of DNA and proteins located at the ends of the chromosome, which play important roles in protecting chromosomes from fusion and degradation. 17,18 Until now, numerous methods have been used to analyze the structure of the human telomeric G-quadruplex in vitro, such as high-resolution solution state NMR, 5,[8][9][10]19 single crystal diffraction, 20 molecular dynamics (MD) simulations, [21][22][23] circular dichroism (CD), 7,22,[24][25][26] fluorescence, 7,27 differential scanning calorimetry (DSC), 28,29 mass spectrometry, 30,31 photon correlation spectroscopy, 32 atomic force microscopy (AFM), [33][34][35] analytical ultracentrifugation (AUC) 7,36-39 and so on. 17,18 Until now, numerous methods have been used to analyze the structure of the human telomeric G-quadruplex in vitro, such as high-resolution solution state NMR, 5,[8][9][10]19 single crystal diffraction, 20 molecular dynamics (MD) simulations, [21]…”

Influence of the single‐strand linker composition on the structural/dynamical properties of a truncated octahedral DNA nano‐cage family

“…Thus, atomistic simulations, able to predict the structural/dynamical properties of nanostructures before experiments, can give useful information concerning the stability of the assembly obtained starting from the predesigned sequences. During the past few years molecular dynamics (MD) atomistic simulations have been successfully used to characterize the structure and the dynamics of Seeman DNA nanostructures, to investigate the properties of a truncated octahedral DNA nano‐cage family, to probe the stability and the dynamical properties of DNA nanocircles, supercoiled DNA structures, or human telomeric G‐quadruplex loops and to investigate the temperature dependent encapsulation mechanism of a DNA nanostructure …”