Dynamic flexibility of protein-inhibitor complexes: A study of the HIV-1 protease KNI-272 complex

The dynamics and flexibility of protein-ligand complexes is central to unde rstanding and predicting binding geometries and energetics. We have calcula ted various measures of the dynamic flexibility of a pseudo-C2-symmetric pr otein, HIV-1 protease, complexed with the asymmetric inhibitor KNI-272 base d on molecular dynamics simulations. This system is expected to be an excel lent candidate for observing asymmetric dynamics between the two monomers d ue to the differences in the interactions between the two monomers of the p rotease and the inhibitor. Experimental methods have thus far been unable t o observe the expected asymmetry in this system. Our calculated results are in excellent agreement with the available experimental data for the main-c hain order parameters from a parallel N-15 NMR study of the same inhibitor- protein complex, as well as the Debye-Waller temperature factors from X-ray crystallography. In our simulations, asymmetry between the monomers is fou nd almost exclusively in the side-chain order parameters of the inhibitor a nd protease (especially residues 84A and 84B), for which experimental data are not yet available. We analyze the dynamic information obtained from the different methods and discuss protein-ligand interactions responsible for the dynamical behavior of the complex.