Dynamics revelation of conformational changes and binding modes of heat shock protein 90 induced by inhibitor associations

Abstract

Heat shock protein 90 (Hsp90) has been an attractive target of potential drug design for antitumor treatment. The current work integrates molecular dynamics (MD) simulations, calculations of binding free energy, and principal component (PC) analysis with scanning of inhibitor-residue interaction to probe the binding modes of inhibitors YK9, YKJ and YKI to Hsp90 and identify the hot spot of the inhibitor-Hsp90 binding. The results suggest that the introductions of two groups G1 and G2 into YKJ and YKI strengthen the binding ability of YKJ and YKI to Hsp90 compared to YK9. PC analysis based MD trajectories prove that inhibitor bindings exert significant effects on the conformational changes, internal dynamics and motion modes of Hsp90, especially for the helix α2 and the loops L1 and L2. The calculations of residue-based free energy decomposition and scanning of the inhibitor-Hsp90 interaction suggest that six residues L107, G108, F138, Y139, W162 and F170 construct the common hot spot of the inhibitor-residue interactions. Moreover the substitutions of the groups G1 and G2 in YKJ and YKI lead to two additional hydrogen bonding interactions and multiple hydrophobic interactions for bindings of YKJ and YKI to Hsp90. This work is also expected to contribute theoretical hints for the design of potent inhibitors toward Hsp90.

Fig. 1. Molecular structures. (A) The YKI-Hsp90 complex is shown in cartoon modes, (B) binding pocket of YKI to Hsp90 is displayed in surface modes and the key residues around the pocket are shown in stick modes. (C), (D) and (E) are the structures of inhibitors YK9, YKJ and YKI.

Fig. 2. Root-mean-square fluctuations (RMSFs) of C_α atoms in Hsp90.

Fig. 3. Cross-correlation maps of the fluctuations of the coordinates for C_α atoms of Hsp90 around the mean positions after the equilibration of MD simulations: (A) the apo Hsp90, (B) the YK9-bounded Hsp90, (C) the YKJ-bounded Hsp90 and (D) the YKI-bounded Hsp90.

Fig. 4. Collective motions corresponding to the first principal component PC1 obtained by performing principal component analysis (PCA) on the equilibrated MD trajectories: (A) the unbounded Hsp90, (B) the YK9-bounded Hsp90, (C) the YKJ-bounded Hsp90 and (D) the YKI-bounded Hsp90.

Fig. 5. Free energy landscapes of Hsp90 constructed using projection of MD trajectories on the first two principal components PC1 and PC2 from the diagonalization of covariance matrix: (A) the apo Hsp90, (B) the YK9-bounded Hsp90, (C) the YKJ-bounded Hsp90 and (D) the YKI-bounded Hsp90.

Fig. 6. Inhibitor–residue interactions calculated by using residue-based free energy decomposition: (A) YK9, (B) YKJ and (C) YKI.

Fig. 7. The function of hydrophobic contacts between inhibitors and Hsp90 vs. the simulation time: (A) YK9, (B) YKJ and (C) YKI.

Fig. 8. Statistical analyses of hydrophobic contacts between inhibitors and separate residues of Hsp90. In the current work, the occupancy is defined as the number of conformations forming the C–C atom contacts accounting for the percentage of the total number of conformations recorded in MD trajectories.

Fig. 9. Key residues of Hsp90 forming hydrophobic contacts with three inhibitors. Key residues and inhibitors are shown in stick modes. A pair of carbon atoms following the default parameters of LIGPLOT in distances are defined as hydrophobic contacts.