Tetrel Bond Affects the Self-Assembly of Acetylcholine and its Analogues and is an Ancillary Interaction in Protein Binding

The -N+(CH3)3 residue is present in acetylcholine (ACh) and in many of its analogues which are used as selective ACh agonist or antagonists for human therapy. The X-ray structures of four ACh derivatives show the presence of short and linear contacts between the C atoms of -N+(CH3)3 groups and lone pair possessing atoms. These contacts can be rationalized as tetrel bonds (TtBs) thanks to their geometric features. Interrogation of the Protein Data Bank suggests that similar -N+-C & sdot;& sdot;& sdot;nucleophile contacts affect the details of the binding of ACh and its derivatives to proteins. Quantum theory of atoms in molecules, noncovalent interaction plot, and natural bond orbital analyses consistently confirm that the -N+-C & sdot;& sdot;& sdot;nucleophile contacts observed in small molecule crystals and in substrate/protein complexes are attractive in nature and can be rationalized as TtBs. TtBs involving methyl groups of the -N+(CH3)3 moiety can be proposed as a new item in the palette of interactions allowing the compounds containing this pharmacophoric unit to bind to their target protein and/or to express their biological/pharmacological properties. Experimental and theoretical findings show that the C atoms of the -N+(CH3)3 moiety of acetylcholine and some analogues form tetrel bonds that are robust enough to assemble cations into supramolecular infinite chains; similar tetrel bonds are present also in substrate/protein adducts, specifically they act as ancillary interactions in the binding of these -N+(CH3)3 containing compounds to proteins. image