Exploring Chloride Selectivity and Halogenase Regioselectivity of the SalL Enzyme through Quantum Mechanical/Molecular Mechanical Modeling

• Published in: Journal of chemical information and modeling Vol. 60; no. 2; pp. 738 - 746
• Main Authors: Pereira, Paulo R. M, Araújo, Jéssica de O, Silva, José Rogério A, Alves, Cláudio N, Lameira, Jerônimo, Lima, Anderson H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.02.2020
• Subjects: Chlorides; Chlorides - chemistry; Chlorides - metabolism; Computer simulation; Fluorination; Fluorine; Free energy; Hydrolases - chemistry; Hydrolases - metabolism; Models, Molecular; Protein Conformation; Quantum mechanics; Quantum Theory; Regioselectivity; Selectivity; Stereoisomerism; Substrate Specificity; Thermodynamics
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.9b01079

The catalytic mechanism of SalL chlorinase has been investigated by combining quantum mechanical/molecular mechanical (QM/MM) techniques and umbrella sampling simulations to compute free energy profiles. Our results shed light on the interesting fact that the substitution of chloride with fluorine in SalL chlorinase leads to a loss of halogenase activity. The potential of mean force based on DFTB3/MM analysis shows that fluorination corresponds to a barrier 13.5 kcal·mol–1 higher than chlorination. Additionally, our results present a molecular description of SalL acting as a chlorinase instead of a methyl-halide transferase.