Investigation of Electrostatic Effects on Enyzme Catalysis: Insights from Computational Simulations of Monoamine Oxidase A Pathological Variants Leading to the Brunner Syndrome.

Abstract

Brunner syndrome is a rare genetic disorder characterized by impulsive aggressiveness and intellectual disability, which is linked to impaired function of the monoamine oxidase A (MAO-A) enzyme. Patients with specific point mutations in the MAOA gene have been reported to exhibit these symptoms, along with notably elevated serotonin levels, which suggest a decreased catalytic performance of the mutated MAO-A enzymes. In this study, we present multiscale molecular simulations focusing on the rate-limiting step of MAO-A-catalyzed serotonin degradation for the C266F and V244I variants that are reportedly associated with pathologies characteristic of the Brunner syndrome. We found that the C266F mutation causes an approximately 18,000-fold slowdown of enzymatic function, which is equivalent to a MAOA gene knockout. For the V244I mutant, a somewhat smaller, yet still significant 300-fold slowdown has been estimated. Furthermore, we conducted a comprehensive comparison of the impact of enzyme electrostatics on the catalytic function of the wild-type (WT) MAO-A and both aforementioned mutants (C266F and V244I), as well as on the E446K mutant investigated in one of our earlier studies. The results have shown that the mutation induces a noteworthy change in electrostatic interactions between the reacting moiety and its enzymatic surroundings, leading to a decreased catalytic performance in all of the considered MAO-A variants. An analysis of mutation effects supported by geometry comparison of mutants and the wild-type enzyme at a residue level suggests that a principal driving force behind the altered catalytic performance of the mutants is subtle structural changes scattered along the entire enzyme. These shifts in geometry also affect domains most relevant to catalysis, where structural offsets of few tenths of an Å can significantly change contribution to the barrier of the involved residues. These results are in full agreement with the reasoning derived from clinical observations and biochemical data. Our research represents a step forward in the attempts of using fundamental principles of chemical physics in order to explain genetically driven pathologies. In addition, our results support the view that the catalytic function of enzymes is crucially driven by electrostatic interactions.