Question

HMG-CoA reductase, a critical enzyme in cholesterol synthesis is the target or statin inhibitors. You are characterizing a possible new inhibitor and want to determine its mode of binding to HMG-CoA reductase. Equilibrium dialysis measurements at 25°C, 30°C, and 37°C yielded dissociation constants (Ks) of 2.5 x 10* M, 1.5 x 10*, and 1.0 x 10* M, respectively, for the HMG- CoA reductase-inhibitor complex a. Is the binding becoming better or worse with increasing temperature? Explain. b. Using Excel or similar program, tabulate the data, make a van't Hoff plot, and use itto determine AAH° and AAS°' for the dissociationreaction c. What are the corresponding AAH°' and AAS°" for complexformation? d. What is AG°' for complex formation at 25° C? e. Is this inhbitor binding driven by entropy or enthalpy? Explain f. What mode of binding (i.e., forces or interactions) would you predict for the inhibitor? What's your rationale?

Answer 1

Page No Soluhon According tothe given data the below Procedube Solution follows ie O Hera HMG- COA + inhiblto <----> HM G-COA - inhibrtoO Seperate the tendence of the tuo ComPonent the DisSocia-tion Conslant af a Reveosible interactian Descibes (ks) dissociatian CHMG-CoA Constant inhibito НMG -cOA inbibito decreases hen heoe is increase in Value Temperatuse-that Shows that Concentration af HMG- COA -inhibito* Complei is Ihereasenq (o) Else Decreasing in HMG - CoA As the TemPeratuae get hised the nhibito io troppe d inside the binding Site of the HMG-COA be cause of Enzyme hang the Con-formationa 1 Changes The Values of DH, DS aTe as follows by taking ito Consideratian of the slope and Inlecept of Ks Vs V Plot

Solution DH 3.8a J JImol 160 93 Ds Complex toomatian the Values aue Foo D H--3- 8 a k Jl t60 93 DS = mol k Jmoles = -41.96 kilo For Complex foomation; AG Hea he Value of AGı foo the complex foomation Called Negative cohich is and that is decrease of the SPontaneoUS ProcesS inhibrto binding is driven by Entoopy. The binding having the Reversability having the demands non -Covalent inteoactions Uke nydrogen bonds, hydrophobic fooces Van Do inteoacton Waals ouo dequioed data is obtained Hence