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.
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