Mechanisms of histone lysine-modifying enzymes: A computational perspective on the role of the protein environment |
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| Affiliation: | 1. Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, UK;2. Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford OX1 3QZ, UK;3. Departamento de Química, Pontifícia Universidade Católica do Rio de Janeiro, RJ 22451-900, Brazil;1. Institut für Physikalische Chemie und Elektrochemie, Wilhelm-Gottfried-Leibniz-Universität Hannover, Callinstraße 3A, 30167 Hannover, Germany;2. Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal 576104, India;3. Departamento de Química Física y Química Inorgánica, Facultad de Ciencias, Universidad de Valladolid, 47011 Valladolid, Spain;1. Department of Physics & Astronomy, Pomona College, Claremont, CA 91711-6359, United States;2. Gottfried-Wilhelm-Leibniz-Universität Hannover, Institut für Physikalische Chemie & Elektrochemie, Callinstraße 3A, 30167 Hannover, Germany;3. Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287-1604, United States;1. Department of Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Daxuecheng South Rd. 55, 401331 Chongqing, China;2. Dipartimento di Chimica “G. Ciamician” dell''Università, Via Selmi 2, I-40126 Bologna, Italy;3. Institut für Physikalische Chemie und Elektrochemie, Gottfried-Wilhelm-Leibniz-Universtät, Callinstr. 3A, D-30167 Hannover, Germany;1. Development, Aging, and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA;2. CELLTRONIX, San Diego, CA 92126, USA;4. Amorphous State Laboratory, Institute of Engineering Technology and Natural Science, Belgorod State University, Belgorod, Russian Federation;5. Department of Reproductive Medicine, University of California, San Diego, La Jolla 92093, CA, USA;6. Department of Pediatrics, University of California, San Diego, La Jolla 92093-0816, CA, USA |
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| Abstract: | 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. |
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| Keywords: | Epigenetics Quantum mechanics/molecular mechanics (QM/MM) Molecular dynamics (MD) Post translational modifications (PTM) Acetyltransferases Methyltransferases Bromodomains Demethylases Deacetylases Chromodomains Tudor domains PHD fingers Energy decomposition analysis (EDA) |
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