Molecular dynamics studies of the HIV-1 TAR and its complex with argininamide

Abstract

The dynamic behavior of HIV-1 TAR and its complex with argininamide is investigated by means of molecular dynamics simulations starting from NMR structures, with explicit inclusion of water and periodic boundary conditions particle mesh Ewald representation of the electrostatic energy. During simulations of free and argininamide-bound TAR, local structural patterns, as determined by NMR experiments, were reproduced. An interdomain motion was observed in the simulations of free TAR, which is absent in the case of bound TAR, leading to the conclusion that the free conformation of TAR is intrinsically more flexible than the bound conformation. In particular, in the bound conformation the TAR-argininamide interface is very well ordered, as a result of the formation of a U.A.U base triple, which imposes structural constraints on the global conformation of the molecule. Free energy analysis, which includes solvation contributions, was used to evaluate the influence of van der Waals and electrostatic terms on formation of the complex and on the conformational rearrangement from free to bound TAR.

Figure 1

Secondary structure of HIV-1 TAR and NMR structures of bound and free TAR.

Figure 2

Free TAR trajectory RMSDs, calculated on all atoms, and local RNA regions (lower stem, bulge, upper stem and loop) relative to the starting structures. Each color refers to one of the three simulations performed.

Figure 3

Bound TAR RMSDs calculated on all heavy atoms and RNA regions (lower stem, bulge, upper stem and loop) relative to the starting structure. Each color refers to one of the three simulations performed.

Figure 4

Interhelical angle traced over the simulations of free TAR (top) and bound TAR (bottom). The horizontal dotted lines indicate the maximum and minimum interhelical angles in the NMR family, while the single squares with error bars are the average angles with standard deviations within the NMR family.

Figure 5

Conformation of the nucleotides in the bulge and surrounding region. On the left is the initial NMR structure by Aboul-ela et al., in the center is the final MD structure and on the right is the X-ray structure of Ippolito and Steitz.

Figure 6

Base triple in bound TAR. (Top) Positions of U23-A27-U38 in the starting structure. (Bottom) The same triple after 270 ps of molecular dynamics simulation. U38-A27 forms a Watson–Crick base pair; U23 is initially far from the pair, but gets closer and co-planar with U38-A27 during the simulation. Hydrogen bonding acceptor–donor distances are reported.

Figure 7

Conformation of the binding pocket for argininamide averaged during the last 600 ps of molecular dynamics simulation. The guanidinium group is stacked between A22 and U23 and hydrogen bonded to G26.

Figure 8

(a) (Top) Tracking the distances between donor and acceptor in U23 and A27 during the simulation of structure 8. (Bottom) Time evolution of the interaction free energy [AB – (A+B)] for structure 8. Electrostatic (electro) and van der Waals terms (vdW) are shown in different colors, the thicker lines representing 3-point running averages. (b) As (a) for structure 1. (c) As (a) for structure 15.