Thermodynamic consequences of Tyr to Trp mutations in the cation–π-mediated binding of trimethyllysine by the HP1 chromodomain

Krone, Mackenzie W.; Albanese, Katherine I.; Leighton, Gage O.; He, Cyndi Qixin; Lee, Ga Young; Garcia‐Borràs, Marc; Guseman, Alex J.; Williams, David C.; Houk, K. N.; Brustad, Eric M.; Waters, Marcey L.

doi:10.1039/d0sc00227e

Cited by 14 publications

(21 citation statements)

References 23 publications

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“…A similar effect is also noted for interactions of ammonium ions with phenol and indole. Consistent with earlier work, [14] we also note that the methylated ammonium ions bind most strongly to indole, followed by phenol and benzene. Overall, we find that in the scenario where methyl groups are added away from the dimer interface, dimer affinities drop substantially.…”

Section: Resultssupporting

confidence: 92%

“…We also examine the effect of ammonium methylation on its dimerization energies with two other aromatic groups, phenol and indole. These molecules represent tyrosines and tryptophans, respectively, found frequently in binding pockets of methyllysine reading domains, [49] and there are ongoing efforts to understand their relative roles in binding and selectivity [12,14] …”

Section: Resultsmentioning

confidence: 99%

“…Lysine N‐methylation does not change lysine‘s positive charge, which is, in fact, important to the binding of methylated lysines to methyllysine binding domains of proteins [8,9] . Experiments also show that the specific length of lysine‘s side chain, [10] as well as the chemistries of aromatic groups present in methyllysine binding sites are important to the binding of methylated lysines [11–14] …”

Section: Introductionmentioning

confidence: 96%

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Methyl‐Induced Polarization Destabilizes the Noncovalent Interactions of N‐Methylated Lysines

Rahman

Wineman-Fisher

Nagy

et al. 2021

Chemistry A European J

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Lysine methylation can modify noncovalent interactions by altering lysine's hydrophobicity as well as its electronic structure. Although the ramifications of the former are documented, the effects of the latter remain largely unknown. Understanding the electronic structure is important for determining how biological methylation modulates proteinÀ protein binding, and the impact of artificial methylation experiments in which methylated lysines are used as spectroscopic probes and protein crystallization facilitators. The benchmarked first-principles calculations undertaken here reveal that methyl-induced polarization weakens the electrostatic attraction of amines with protein functional groups -salt bridges, hydrogen bonds and cation-π interactions weaken by as much as 10.3, 7.9 and 3.5 kT, respectively. Multipole analysis shows that weakened electrostatics is due to the altered inductive effects, which overcome increased attraction from methyl-enhanced polarizability and dispersion. Due to their fundamental nature, these effects are expected to be present in many cases. A survey of methylated lysines in protein structures reveals several cases in which methyl-induced polarization is the primary driver of altered noncovalent interactions; in these cases, destabilizations are found to be in the 0.6-4.7 kT range. The clearest case of where methyl-induced polarization plays a dominant role in regulating biological function is that of the PHD1-PHD2 domain, which recognizes lysine-methylated states on histones. These results broaden our understanding of how methylation modulates noncovalent interactions.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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Methyl‐Induced Polarization Destabilizes the Noncovalent Interactions of N‐Methylated Lysines

Rahman

Wineman-Fisher

Nagy

et al. 2021

Chemistry A European J

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“…2b). These results implicated that Trp and Arg were essential in the cation-π and π-cation interactions, which was consistent with the previous results [33][34][35].…”

Section: Data Content and Analysissupporting

confidence: 93%

A Comprehensive Analysis of Protein Data Bank reveals Low Desolvation Penalty in π-Cation System

Yang

Wang

et al. 2020

Preprint

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Cation-π interactions widely exist between ligand-protein interfaces, attracting much attention in molecular recognition in recent years. Interactions named cation-π and π-cation (cationic vs arene small molecular ligands) shall be separately considered in drug and pesticide design process. The two interactions involved in ligands and protein pockets may differ in energy features and therefore offers significant inspiration for drug and pesticide design. However, an in-depth study on differences between cation-π and π-cation systems from an energy perspective is still lacking. In this study, we calculated and compared cation-π and π-cation systems in terms of physicochemical properties of ligand/protein and solvation effect. It seems that the desolvation penalty of the cation-π systems was relatively higher than the π-cation pairs, even though these interactions both can improve the ligand activity. This is the reason for evolution converged on π-cation interactions in the cation-π-mediated proteins. The π-cation interaction facilitating the inhalation of ligand to the pocket may provide a new sight for the molecular design of pharmaceuticals and pesticides.

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“…HP1′s aromatic cage residues were individually substituted on position 24 and 48 with tyrosine analogues to further establish the individual contributions of these two residues in recognition of Kme3, revealing that the residues do not equally contribute towards cation–π binding and that efficient association depends on contact between Tyr residues and Kme3 [ 152 ]. Additionally, the Tyr residues present in the HP1 aromatic cage were substituted by Trp to investigate if this mutation could increase the binding strength to the Kme3-containing substrate, and more generally the conservation of aromatic residues within aromatic cages [ 153 ]. It was found that the mutation Y24W was not perturbing and allowed in the binding pocket, leading to a −5 kcal mol −1 stronger binding.…”

Section: Reading Kme3mentioning

confidence: 99%

Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

Maas

Hintzen

Porzberg

et al. 2020

IJMS

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Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.

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Thermodynamic consequences of Tyr to Trp mutations in the cation–π-mediated binding of trimethyllysine by the HP1 chromodomain

Abstract: In this work, we experimentally validate that tryptophan provides the strongest cation–π binding interaction among aromatic amino acids and also lend insight into the importance of residue identity in trimethyllysine recognition by reader proteins.

Cited by 14 publications

References 23 publications

Methyl‐Induced Polarization Destabilizes the Noncovalent Interactions of N‐Methylated Lysines

Methyl‐Induced Polarization Destabilizes the Noncovalent Interactions of N‐Methylated Lysines

A Comprehensive Analysis of Protein Data Bank reveals Low Desolvation Penalty in π-Cation System

Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

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