Cation–π interactions of methylated ammonium ions: A quantum mechanical study

Abstract

Cation-π interactions of methylated ammonium ions play a key role in a broad range of biochemical systems. These include methyl-lysine binding proteins which bind to methylated sites on histone proteins, lysine demethylase enzymes which demethylate these sites, and neurotransmitter receptor complexes which bind choline derived ligands. Recognition in these systems is achieved through an ‘aromatic cage’ motif in the binding site. Here we use high level quantum mechanical calculations to address how cation-π interactions of methylated ammonium ions are modulated by a change in methylation state and interaction geometry. We survey methyl-lysine and choline derived complexes in the Protein Databank to validate our results against available structural data. A quantitative description of cation-π interactions of methylated ammonium systems is critical to structure-based efforts to target methyl-lysine binding proteins and demethylase enzymes in the treatment of unregulated transcriptional control, and neurotransmitter receptors in the treatment of neurological disease. It is our hope that our work will serve as a benchmark for the development of physical chemistry based force fields that can accurately model the contribution of cation-π interactions to binding and specificity in these systems.

Improving the Force Field Description of Tyrosine–Choline Cation−π Interactions: QM Investigation of Phenol–N(Me)4+ Interactions

“…This is a slightly less favorable interaction energy than the −19 kcal mol −1 calculated by Rapp et al . using DFT (M06-2X/6–31++G**) 27 or the −17.58 kcal mol −1 reported by Orabi et al . 52 using MP2(FC)/6–311++G(d,p).…”

K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site

“…a–c, 2F o -F c densities (blue) for a, K 2P 2.1(TREK-1):ML335 (1.5 σ), b, K 2P 2.1(TREK-1):ML402 (1.0 σ), and c, K 2P 2.1(TREK-1) (1.0 σ). Offset angle for the cation-π interactions for Lys271:ML335 and Lys271:ML402 is shown and adopts an oblique geometry common to cation-π interactions 35 , 36 . d, and e, F o -F c densities (hotpink, 3.0 σ) for d, K 2P 2.1(TREK-1):ML335 and e, K 2P 2.1(TREK-1):ML402.…”

Alkaloids of Abuta panurensis Eichler: In silico and in vitro study of acetylcholinesterase inhibition, cytotoxic and immunomodulatory activities

“…The first one is between the positively charged quaternary ammonium nitrogen and a carboxylic group of the Glu199. The second interaction is formed between the same charged nitrogen atom and a phenyl ring of the Trp84, at a distance of approximately 4.4 Å, typical for tetraalkylammonia-π interactions [90] (Fig 5).…”