QM-cluster model study of CO₂ hydration mechanisms in metal-substituted human carbonic anhydrase II

Abstract

Human carbonic anhydrase (CA) metalloenzymes utilize a Zn2+-containing active site to catalyze the interconversion of carbon dioxide to bicarbonate. The Zn2+ may be replaced with other divalent transition metals, though the catalytic efficiency of the enzyme will be reduced. In this work, quantum mechanical cluster models of the active site are used to map the reaction profile for the hydration mechanism of carbon dioxide. The Lipscomb proton transfer and Lindskog rotation mechanisms were examined for the native Zn2+-enzyme along with variants where the metal was substituted with Cd2+, Ni2+, Fe2+, and Fe3+. The findings highlight the impact the metal coordination geometry has on the reaction profile. The results also suggest Fe2+, which is the functional metal for a prototypical CA of an anaerobic bacterium, might also be functional for human CA if cultured within an anaerobic environment.

Benchmarking Density Functional Theory Methods for Metalloenzyme Reactions: The Introduction of the MME55 Set

“…M06 and M062X were developed simultaneously, but the fitting set for M06 contained an additional database of transition-metal bond energies so it is generally better for organometallic systems. B3LYParguably the most popular hybrid DFA for molecular quantum chemistryis regularly used for mechanistic studies of metalloenzymes, ,,,,– often uncorrected or with the older DFT-D2 or -D3(0) dispersion corrections. B3LYP-D3­(BJ), however, only comes in 12th place and is outperformed by the best functional in the rung below [MN15-L-D3(0)].…”

Benchmarking Density Functional Theory Methods for Metalloenzyme Reactions: The Introduction of the MME55 Set

“…M06 and M062X were developed simultaneously, but the fitting set for M06 contained an additional database of transition metal bond energies 136 so it is generally better for organometallic systems. B3LYParguably the most popular hybrid DFA for molecular quantum chemistry-is regularly used for mechanistic studies of metalloenzymes, 69,73,169,170,[186][187][188][189][190] often uncorrected or with the older DFT-D2 191 or -D3(0) dispersion corrections. B3LYP-D3(BJ), however, only comes in 12th place, and is outperformed by the best functional in the rung below [MN15-L-D3(0)].…”

Benchmarking Density Functional Theory Methods for Metalloenzyme Reactions: The Introduction of the MME55 Set

“…The ranges of PDs for these two functionals are also impressive, with no significant tails in either direction. Despite B3LYP still being regularly used for mechanistic studies of metalloenzymes, 62,66,152,160,163,[179][180][181][182][183][184][185] often uncorrected or with the older DFT- For the double hybrids, the deviations and PDs with the largest magnitudes mostly come from the two copperdependent enyzmes Hc and Mo-Cu CODH, because MP2 is particularly problematic for copper complexes, as mentioned earlier. It massively overstabilizes the peroxo geometry of the Cu 2 O 2 core in the singlet state, 41 leading to the large negative deviations and PDs seen for Hc 1RE2 which corresponds to the formation of that configuration-the PD of this step for MP2 is −652.9%, while the average PD across the double hybrids is −284.9%.…”