ATP and its N⁶-substituted analogues: parameterization, molecular dynamics simulation and conformational analysis

Abstract

In this work we used a combination of classical molecular dynamics and simulated annealing techniques to shed more light on the conformational flexibility of 12 adenosine triphosphate (ATP) analogues in a water environment. We present simulations in AMBER force field for ATP and 12 published analogues [Shah et al. (1997) Proc Natl Acad Sci USA 94: 3565-3570]. The calculations were carried out using the generalized Born (GB) solvation model in the presence of the cation Mg(2+). The ion was placed at a close distance (2 Å) from the charged oxygen atoms of the beta and gamma phosphate groups of the -3 negatively charged ATP analogue molecules. Analysis of the results revealed the distribution of inter-proton distances H8-H1' and H8-H2' versus the torsion angle ψ (C4-N9-C1'-O4') for all conformations of ATP analogues. There are two gaps in the distribution of torsion angle ψ values: the first is between -30 and 30 degrees and is described by cis-conformation; and the second is between 90 and 175 degrees, which mostly covers a region of anti conformation. Our results compare favorably with results obtained in experimental assays [Jiang and Mao (2002) Polyhedron 21:435-438].

Figure

Dihedral O4′–C1′–N9–C4 angle dependence on inter-proton distances H8–H1′ (crosses) and H8–H2′ (dots) measured for ATP

Fig. 1

Distance restraints held the magnesium cation (Mg²⁺) close to the charged oxygen atoms (atom types O1B, O1G, O2B and O2G) of the phosphates (2.0–4.5 Å)

Fig. 2

Time/temperature dependence during single simulated annealing molecular dynamics (MD) run. The simulated annealing (SA) protocol is shown in the box

Fig. 3

Dihedral O4′–C1′–N9–C4 angle dependence on inter-proton distances H8–H1′ (crosses) and H8–H2′ (dots) measured for ATP (a) and its analogues (b). This plot can be compared to the plot presented by Jiang et al. [24], the results of which were obtained from crystallography and NMR system (CNS) experiments

Fig. 4

Distances between the magnesium cation (Mg²⁺) and oxygen atoms from beta and gamma phosphate groups (O1B, O1G, O2B and O2G) in each of the MD runs, calculated for ATP

Fig. 5

Distribution of values of the dihedral angle O4′–C1′–N9–C4, partially defining the conformation of ATP obtained in 1,000 MD runs. There are two maxima, first present around −120 degrees (conformation anti) and the second around 60 degrees (conformation syn)

Fig. 6

Dihedral O4′–C1′–N9–C4 angle dependence on sugar conformation, described by dihedral C1′–C2′–C3′–C4′angle measured for ATP (a) and its analogues (b). In a, the schematic conformational transition from inactive to active state is also shown. The conformations were not clustered but we indicate only those that were close to each other (black boxes in a)