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

 Hinge-bending sites and inhibitor efficiency

• Mobilities m_i = [(ΔR_i)²]₁/(<z>/z_i)]^1/2 of p66 residues (1 < i < 560) in the first  mode (continuous curve; right ordinate) compared with the separation (l_i) of individual residues from drug-binding site (curve with open circles, left ordinate). z_i is the coordination number of residue i, <z> is the average over all z_i. The superposition of the curves in 1 < i < 311 (all p66 subdomains, excluding the connection and RNase H domain) evidences the binding of the drug to the global hinge center that coordinates the movements of the p66 fingers and thumb. The inset shows the correlation between m_i and l_i.
  

• The close superposition of the m_i and l_i curves at the thumb, palm and fingers of subunit p66. Thus, the mobilities of these three subdomains scale linearly with their separation from the drug binding site, after eliminating the perturbations introduced by local density fluctuations.
  

• The physical meaning of this observation is that the drug precisely binds to the hinge site that coordinates the movements of these subdomains.

• (A) Two hinge-bending centers on RT forming minima in Figure 1 (or 4): (I) near the NNRTI binding site, involving residues 107-110 (cyan), 161-165 (green), 180-188 (red) and 219-231 (blue), and (II) near the p66 connection and RNase H interface, comprising residues 363-366 (cyan), 394-408 (green), 410-423 (loop, magenta), 424-429 (interdomain linker, red), and 504-512 (yellow). (B) A closer view of region II, showing explicitly the side chains near the hinge site. Close tertiary contacts are indicated by the yellow dots.

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