The interaction between methionine and two aromatic amino acids is an abundant and multifunctional motif in proteins

Many types of non-covalent interactions give rise to a protein's natural structure and function. One such interaction involves an aromatic amino acid (phenylalanine (Phe), tryptophan (Trp), or tyrosine (Tyr)) and the sulfur of methionine (Met), the so-called methionine-aromatic interaction. The Met-aromatic interaction is well-established, and it is defined as involving one aromatic and one Met residue. However, in a small-scale survey, we recently noted that more than one aromatic residue can interact with one Met in a "bridging" motif of the general form Aro-Met-Aro. In the present work, a systematic survey of all protein structures available in the Protein Data Bank was carried out. About 70% of those structures contain any Met-aromatic interaction and over 40% contain a Met-aromatic bridge. Analysis of a smaller subset of protein structures, which omits entries with low resolution or high sequence homology, shows the same distribution. The relationship of bridging interactions and longer aromatic amino acid chains also was explored using network theory approaches. Met-Aro bridges were found in 8.4% of extended aromatic chains. Analysis of a different subset of proteins that contain embedded metal ions as reference points revealed that many Met-Aro bridges are at/near protein surfaces. These analyses, and some specific examples, lead to the proposal that Met-aromatic bridges play biological roles as stabilizers and protectors of protein structures, motifs for molecular recognition, and electron transfer mediators.