Energy enzyme-inhibitor complex

Free Energy Calculations on Enzyme-Inhibitor Complexes Studies of Thermolysin and Rhizopus Pepsin... 

Figure 1. CADD Flowchart. "E I = enzyme-inhibitor complex. Ascan binding interactions using strategy described in reference 16. T and I are structurally similar, relative energies or estimated relative free energies.

Enzyme-Inhibitor Complexes Using a Preference-Based Free-Energy Surface. 

The lower the value, the better the inhibitor, given that the equilibrium lies more in favor of enzyme-inhibitor complex formation. The affinity of an inhibitor for an enzyme may be related to the standard free energy (AG ") of a system by Equation 17.3. 

Hydrolysis of phosphate esters is one of the fundamental biochemical reactions and a vast amount of research has been devoted to the study of phosphoryl transfer reactions [57-60], both in solution and in enzymes. Despite these efforts there are still ambiguities regarding the interpretation of experimental data (e.g., linear free energy relationships, kinetic isotope effects, crystal structures of enzyme-inhibitor complexes etc.) in terms of detailed reaction mechanisms [21,25,59,60]. Of particular interest has been to determine... 

Pincus, M. R. and Scheraga, H. A. (1979) Conformational energy calculations of enzyme-substrate and enzyme-inhibitor complexes of lysozyme. 2. Calculation of the structures of complexes with a flexible enzyme., Macromolecules 12, 633-644. 

A. Wallqvist and D. G. Covell. Docking enzyme-inhibitor complexes using a preference-based free-energy surface. PROTEINS Structure, Function and Genetics, 25 403-419,... 

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. 

Figure 2 Two thermodynamic models that link perturbations in enzyme-inhibitor binding equilibria to values for interaction energies. E, enzyme I, inhibitor E l, enzyme-inhibitor complex AAGinteract energetic contribution of the perturbed interaction to complex formation AGso1v,e energy of desolvation for the enzyme AGsoiv, energy of desolvation for the inhibitor AGresoiv, energy of resolvation of the E l complex.

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