Abstract
We report a hybrid quantum mechanics/molecular mechanics theoretical study on the reaction mechanism of mammalian histidine decarboxylase that allows us to obtain valuable insights on the structure of the cofactor-substrate adduct (external aldimine) in the active site of rat histidine decarboxylase. By means of molecular dynamics simulations, we traced the potential of mean force corresponding to the decarboxylation reaction of the adduct both in the active site of the enzyme and in aqueous solution. By comparing this process in both media, we have identified the key electrostatic interactions that explain the lowering of the free energy barrier in the enzyme. Our analysis also offers a validation of Dunathan's hypothesis (Dunathan, H. (1966) Proc. Natl. Acad. Sci. U. S. A. 55, 712-716) regarding the role of stereoelectronic effects in the enzymatic decarboxylation process.
Highlights
Computational approaches to investigation of enzymatic catalysis rely on the ability to obtain a proper initial structure for the system under study
We report a hybrid quantum mechanics/molecular mechanics theoretical study on the reaction mechanism of mammalian histidine decarboxylase that allows us to obtain valuable insights on the structure of the cofactor-substrate adduct in the active site of rat histidine decarboxylase
Three-dimensional structures are best determined by experimental methods such as x-ray diffraction, nuclear magnetic resonance (NMR) spectroscopy, or even electron microscopy [1]
Summary
Computational approaches to investigation of enzymatic catalysis rely on the ability to obtain a proper initial structure for the system under study. A homology model for the structure of rat histidine decarboxylase reported by the authors [18] and validated by directed mutagenesis [3, 21] was used to manually fit the Schiff base formed by the histidine substrate and the cofactor PLP into the active cleft in two different ways; this was done to obtain the two starting conformations of the external aldimine.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
