Deacetylation mechanism of histone deacetylase 8: insights from QM/MM MP2 calculations

• DOI: 10.1039/d5cp00002e
• Publication Date: 2025-03-10T21:01:21Z
• Authors: Rui Lai; Hui Li
• Keywords: QM/MM

Understanding the catalytic mechanism of histone deacetylases can greatly benefit development targeted therapies that are safe and effective. Combined quantum mechanical molecular (QM/MM) Møller-Plesset second-order perturbation theory (MP2) geometry optimizations performed to investigate deacetylation reaction a tetrapeptide catalyzed by human Histone Deacetylase 8. A three-step is identified: first step formation negatively charged tetrahedral intermediate via nucleophilic addition activated water amide C atom proton transfer from His143; second neutral with an elongated C-N bond His143 N atom. The third complete cleavage bond, accompanied newly formed carboxylic group His142. These three steps have similar computed energy barriers, having highest calculated activation free 19.6 kcal mol-1. When there no potassium ion at site 1, 17.7 Both values in good agreement experimental value 17.5 Their difference implies would be 25-fold increase enzyme's activity, line experiments. solvent hydrogen-deuterium kinetic isotope effect was ∼3.8 for both cases. It also found barriers significantly systematically higher on QM/MM B3LYP B3LYP-D3 potential surfaces. In particular, methods fail predict meaningful transition state step, leading two-step mechanism. With sufficiently large basis set such as aug-cc-pVDZ, M05-2X, M06-2X, M06, MN15 give results much closer MP2 method. However, when smaller 6-31G* used, these lead errors 10 mol-1 pathway. highlight importance using accurate QM computational study enzyme catalysis.