Factors determining the enzyme catalytic power caused by noncovalent interactions: Charge alterations in enzyme active sites

Key difference between transition state stabilization and ground state destabilization: increasing atomic charge densities before or during enzyme–substrate binding

“…In a previous study, we reported that enzymes reduce the Δ G ‡ s of reactions by decreasing positive charges and/or increasing negative charges in the electron-donating centers, as well as by decreasing negative charges and/or increasing positive charges in the electron-accepting centers of the reactions. 39 We further demonstrate the relationship between the Δ G ‡ reduction mechanism identified in this study and the charge alteration mechanism. As shown in Fig.…”

“…The effect of the R ‡ ⋯E interaction on the difference between Δ G ‡ cat and Δ G ‡ uncat , which is expressed by ΔΔ G ‡ RE , represents the free energy change of the following H-bond pairing process as has been shown in previous studies. 33,34,39 R ‡ ⋯W + R⋯E ⇌ R ‡ ⋯E + R⋯WΔΔ G ‡ RE = −( H E − H W )( H R‡ − H R )/7.02where H R , H R‡ H E , and H W represent the H-bonding capabilities of R, R ‡ , E and W, respectively. H-bonding capability is a critical parameter for correctness in eqn (2).…”

“…Only the interactions of the substrate atoms experiencing a charge density alteration, which includes the substrate oxygen atom and the a-H, change during the reaction process and affect the DG ‡ of the reaction, as demonstrated in previous studies. 33,39 Thus, we focus our investigation on the interactions of substrate atoms that experience a charge alteration to evaluate their role in DG ‡ reduction. For the sake of completion, we also consider the roles of the interactions of substrate atoms without charge density alterations.…”

“…The effect of the R ‡ /E interaction on the difference between DG ‡ cat and DG ‡ uncat , which is expressed by DDG ‡ RE , represents the free energy change of the following H-bond pairing process as has been shown in previous studies. 33,34,39…”

“…34 The accuracy of using eqn (2) to explore the catalytic power contributed by enzyme-substrate interactions were validated using reported experimental data and via a theoretical derivation. 33,39 For the R/E interaction to contribute to enzyme catalytic power, DDG ‡ RE must be less than 0. Thus, eqn (2) can be used to demonstrate whether the common DG ‡ reduction mechanism applies to all noncovalent interactions of the substrate atoms experiencing a charge density alteration.…”