Triplex hydration: nanosecond molecular dynamics simulation of the solvated triplex formed by mixed sequences

Abstract

A theoretical model for the hydration pattern and motion of ions around the triple helical DNA with mixed sequences d(GACTGGTGAC)d(GTCACCAGTC)*d(GACTGGTGAC) in solution, during MD simulation, using the particle mesh Ewald sum method, is elaborated here. The AMBER 5.0 force field has been used during the simulation in solvent. The simulation studies support a dynamically stable atmosphere around the DNA triplex in solution over the entire length of the trajectory. The results have been compared with Hoogsteen triplexes and examined in the context of the observed behaviour of hydration in crystallographic data of duplexes. The dynamical organization of counterions and water molecules around the triplex formed by mixed sequences is described here. It has been observed that cations prefer to bind between two adjoining purines of the second and the third strands. The idea of localized complexes (mobile counterions in unspecific electronegative pockets around the DNA triplex with water molecules) may have important implications for understanding the specificity of the interactions of nucleic acids with proteins and other ligands.

Figure 1

A snapshot of the DNA triplex with water molecule within 3 Å from the DNA surface. Some of the water molecules are shown as a ball and stick model. Both hydrogens of these molecules are involved in hydrogen bonding with the DNA triplex. The triplex is shown as a stick model in which, for the duplex, stick size is 0.3 while for the third strand, it is 0.2 [key: first strand, red; second strand, violet and third strand, yellow; water, white and ions, blue].

Figure 2

Variation of cylindrical distribution function g(R) and running coordination number Nc(R) with distance of the Na⁺ ions from the triplex surface around the DNA helical axis.

Figure 3

A snapshot of the position of counterions during simulation. The ions are shown in blue, water in white and all the bases are in different colours. (a) Position of 33rd ion in the T7pG8 pocket of the backbone. (b) Position of 37th ion near the N7 atom of A29 residue of third strand in the G28pA29 pocket. (c) Position of 41st ion close to the N7 atoms of A17, G18 of second strand and G21, A22 of third strand. (d) Position of 42nd ion near the N7 atoms of A14 of second strand and G25, G26 of third strand.

Figure 4

Average structure of the DNA triplex for 1000–1600 ps simulation. The Na⁺ ions within 5 Å distance are also shown. The duplex and ions are shown in CPK, while the third strand is shown in the stick model. All are in different colours (1st, first strand; 2nd, second strand and 3rd, third strand).

Figure 5

The structure of base triplets from the average minimized structure of the DNA triplex.