Protein-inhibitor complexes, conformational energies

Another potent inhibitor of DHFR is trimethoprim. The crystal structures of two enzyme-inhibitor complexes (DHFR from Escherichia coli and chicken liver) have been determined [87]. Surprisingly, the inhibitor adopts different conformations in the two proteins. In the chicken liver enzyme, a butterfly-like conformation is observed (t,/t2 = -85°/102 ) in the bacterial enzyme, the aromatic rings are oriented nearly perpendicular to each other ( twisted conformation, r,/T2 = 177°/76°). The inhibitor shows higher affinity for the bacterial enzyme, and the lower energy of the twisted conformation may be partially responsible for this. 

Fig. 2. Conformational free energy of closed, intermediate and open protein kinase conformations. cAPK indicates the unbound form of cAMP-dependent protein kinase, cAPKiATP the binary complex of cAPK with ATP, cAPKiPKP the binary complex of cAPK with the peptide inhibitor PKI(5-24), and cAPK PKI ATP the ternary complex of cAPK with ATP and PKI(5-24). Shown are averaged values for the three crystal structures lATP.pdb, ICDKA.pdb, and ICDKB.pdb. All values have been normalized with respect to the free energy of the closed conformations.

Figure 3 The frequency of predicting the crystal structure of the SB203386-HIV-1 protease complex in docking simulations with the ensemble of 6 protein conformations (a) and the ensemble of 32 protein conformations (b). The RMSD of the docked inhibitor conformations from the crystal structure ranked by energy in simulations with the ensemble of 6 protein conformations (c) and the ensemble of 32 protein conformations (d). The piecewise linear energy function is employed.

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