Inhibitor binding alters the directions of motions in HIV-1 reverse transcriptase

• Ligand binding has minor effect on the size of residue motions

• The global mode shapes of unliganded (solid), nevirapine bound (dashed), efavirenz bound (dotted) RT.
  

• Small difference is observed in the fluctuation behaviors of the wild type RT and the RTs complexed with NNRTIs.
  

• p66 fingers, thumb and RNase H subdomains and p51 thumb subdomain undergo high amplitude fluctuations.
  

• The palm and connection subdomains of p66, on the other hand, are severely constrained. Minima at the palm and connection indicate the regions acting as hinge-bending sites in the global mode.

• Fluctuating conformations of the nevirapine-bound (A) and unliganded  (B) forms of RT. The left (I) and right (II) diagrams are the conformations between which the molecule fluctuates, as derived by the ANM computation of global dynamics. The p66 subdomains are colored cyan (fingers), yellow (palm), red (thumb), green (connection) and pink (RNase H).
  

• The most striking aspect of Figure 2 is the  difference in the mechanisms of global fluctuations for the liganded and unliganded RT. This difference is significant given that the sizes or distributions of fluctuations were practically unaffected by ligand binding (see the first figure).

• The components of fluctuations along X, Y, and Z directions for unliganded(solid) and  nevirapine-bound (dashed) RT. See the ribbon diagrams in Figure 3 for the definitions of the X-, Y- and Z-axes.
  

• Drug binding hinders certain domains reorientations.
  

• The out-of-plane fluctuations of all domains, except for p66 thumb, are suppressed in the ligand-bound form (X-direction); in the unliganded form the p66 fingers and thumb fluctuate in opposite direction with respect to the RNase H and p51 thumb, allowing for a cooperative enlargement or contraction of the nucleotide processing cavity between these two regions.
  

• The p66 fingers tend to be decoupled from the p66 thumb in the presence of nevirapine. See the sharp extrema at the p66 fingers in Y-direction, and the inversion in the direction of fluctuations in Z-direction.

Back to HIV RT domain motions