Reaction path analysis for demethylation process of histone tail lysine residues

Histone proteins control many crucial cell regulatory processes post-translational modifications. Among these modifications, methylation is recently shown to be reversible with the discovery of Lysine-specific Demethylase (LSD1) enzyme. As many studies have showed the relation of some cancer-type and other diseases with the abnormalities in the balance of methylation/demethylation, drug molecule design based on the information gained from reaction path analysis becomes very useful. In this paper, a chemically-consistent reaction mechanism is proposed for the demethylation of histone tail lysine residues and the reaction path analysis of this mechanism is carried out. Potential and free energy profiles of the system, which does not include the residues of the enzyme, are calculated with semi-empirical and quantum mechanical (QM) methods. These results create a fundamental basis for further analysis of the demethylation process with enzyme and/or inhibitor molecules available in the literature.