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Updated: May 10, 2026

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine
Published on: February 16, 2018
Concerted hydrogen atom and electron transfer mechanism for catalysis by lysine-specific demethylase
Tao Yu1, Masahiro Higashi, Alessandro Cembran
1Department of Chemistry, Chemical Theory Center, and Supercomputing Institute, 207 Pleasant Street SE, University of Minnesota, Minneapolis, Minnesota 55455-0431, United States.
Abstract:
We calculate the free energy profile for the postulated hydride transfer reaction mechanism for the catalysis of lysine demethylation by lysine-specific demethylase LSD1. The potential energy surface is obtained by using combined electrostatically embedded multiconfiguration molecular mechanics (EE-MCMM) and single-configuration molecular mechanics (MM). We employ a constant valence bond coupling term to obtain analytical energies and gradients of the EE-MCMM subsystem, which contains 45 quantum mechanics (QM) atoms and which is parametrized with density functional calculations employing specific reaction parameters obtained by matching high-level wave function calculations. In the MM region, we employ the Amber ff03 and TIP3P force fields. The free energy of activation at 300 K is calculated by molecular dynamics (MD) umbrella sampling on a system with 102,090 atoms as the maximum of the free energy profile along the reaction coordinate as obtained by the weighted histogram analysis method with 17 umbrella sampling windows. This yields a free energy of activation of only 10 kcal/mol, showing that the previously postulated direct hydride transfer reaction mechanism is plausible, although we find that it is better interpreted as a concerted transfer of a hydrogen atom and an electron.
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