Comparison of molecular recognition of trimethyllysine and trimethylthialysine by epigenetic reader proteins

Jordi C.J. Hintzen, Jordi Poater, Kiran Kumar, Abbas H.K. Al Temimi, Bas J.G.E. Pieters, Robert S. Paton*, F. Matthias Bickelhaupt, Jasmin Mecinović

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Gaining a fundamental insight into the biomolecular recognition of posttranslationally modified histones by epigenetic reader proteins is of crucial importance to understanding the regulation of the activity of human genes. Here, we seek to establish whether trimethylthialysine, a simple trimethyllysine analogue generated through cysteine alkylation, is a good trimethyllysine mimic for studies on molecular recognition by reader proteins. Histone peptides bearing trimethylthialysine and trimethyllysine were examined for binding with five human reader proteins employing a combination of thermodynamic analyses, molecular dynamics simulations and quantum chemical analyses. Collectively, our experimental and computational findings reveal that trimethylthialysine and trimethyllysine exhibit very similar binding characteristics for the association with human reader proteins, thereby justifying the use of trimethylthialysine for studies aimed at dissecting the origin of biomolecular recognition in epigenetic processes that play important roles in human health and disease.

Original languageEnglish
Article number1918
Pages (from-to)1-14
Number of pages14
Issue number8
Early online date21 Apr 2020
Publication statusPublished - Apr 2020


The more stabilizing intrinsic interaction energy of TRP2 with KCme3 (∆Eint = –29.5 kcal mol–1) than with Kme3 (∆Eint = –27.6 kcal mol–1) is further analyzed using quantitative Kohn–Sham molecular orbital (KS-MO) and an associated canonical energy decomposition analysis (EDA); see Table 2. This analysis reveals more favorable electrostatic, orbital and dispersion interactions as the origin of the stronger interaction ∆Eint term in TRP2–KCme3. The more attractive electrostatic interaction ∆Velstat is due to the presence of the negatively charged sulfur atom, which comes in close proximity to the positively charged H atoms of one of the TRP units (see the Voronoi Deformation Density (VDD) charges in Figure 4A). This is also supported by the molecular electrostatic potential isosurfaces for Kme3, KCme3 and TRP2 (Figure 4B) [30,31]. The S atom in KCme3 appears redder (more towards negative), whereas its trimethylated group is bluer (more positive) than for Kme3, which favors the interaction of the former with TRP2. Funding: This work was supported by the European Research Council (ERC Starting Grant, ChemEpigen−715691 to J.M.), Spanish MINECO (CTQ2016–77558-R and MDM−2017–0767 to J.P.), the Generalitat de Catalunya (2017SGR348 to J.P.) and a World Bank Education Grant to K.K.

FundersFunder number
World Bank Group
Horizon 2020 Framework Programme715691
European Research Council
Generalitat de Catalunya2017SGR348
Ministerio de Economía y CompetitividadCTQ2016–77558-R, MDM−2017–0767


    • Epigenetics
    • Histone
    • Lysine methylation
    • Molecular recognition
    • Noncovalent interactions


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