X-ray structure and conformational dynamics of the HIV-1 protease in complex with the inhibitor SDZ283-910: Agreement of time-resolved spectroscopy and molecular dynamics simulations

Based on the X-ray structure of the human immunodeficiency virus type-1 (HI V-1) protease in complex with the statine-derived inhibitor SDZ283-910, a 5 42 ps molecular dynamics trajectory was computed. For comparison with the 8 05 ps trajectory obtained for the uncomplexed enzyme, the theoretical fluor escence anisotropy decay of the unliganded protease and the inhibitor compl ex was calculated from the trajectories of the Trp6A/Trp6B and Trp42A/Trp42 B transition dipole moments. This enabled us to directly compare the simula ted data with the experimental picosecond time-resolved fluorescence data. Fitting both experimental and simulated data to the Kohlrausch-Williams-Wat ts (KWW) function exp(-t/tau(k))(beta) revealed a;very good agreement for t he uncomplexed protease as well as for the SDZ283-910 complex. Binding of t he inhibitor induced a faster decay of both the experimental and the comput ed protease fluorescence anisotropy decay. By this integrative approach, th e atomic detail of inhibitor-induced changes in the conformational dynamics of the HIV-1 protease was experimentally verified and will be used for fur ther inhibitor optimisation. (C) 1999 Academic Press.