Mechanisms of histone lysine-modifying enzymes: A computational perspective on the role of the protein environment

Epigenetic pathways are involved in a wide range of diseases, including cancer and neurological disorders. Specifically, histone modifying and reading processes are the most broadly studied and are targeted by several licensed drugs. Although there have been significant advances in understanding the mechanistic aspects underlying epigenetic regulation, the development of selective small-molecule inhibitors remains a challenge. Experimentally, it is generally difficult to elucidate the atomistic basis for substrate recognition, as well as the sequence of events involved in binding and the subsequent chemical processes. In this regard, computational modelling is particularly valuable, since it can provide structural features (including transition state structures along with kinetic and thermodynamic parameters) that enable both qualitative and quantitative evaluation of the mechanistic details involved. Here, we summarize knowledge gained from computational modelling studies elucidating the role of the protein environment in histone-lysine modifying and reading mechanisms. We give a perspective on the importance of calculations to aid and advance the understanding of these processes and for the future development of selective inhibitors for epigenetic regulators.