Characterization of aromatic-thiol pi-type hydrogen bonding and phenylalanine-cysteine side chain interactions through ab initio calculations and protein database analyses

In this study, the aromatic-thiol pi hydrogen bonding and phenylalanine-cys teine side chain interactions are characterized through both molecular orbi tal calculations on a C6H6-HSCH3 model complex and database analyses of 609 X-ray protein structures. The aromatic-thiol pi hydrogen bonding interacti on can achieve a stabilization energy of 2.60 kcal mol(-1), and is stronger than the already documented aromatic-hydroxyl and aromatic-amino hydrogen bonds. However, the occurrence of the aromatic-thiol hydrogen bond is rathe r rare in proteins. This is because most of the thiol groups participate in the formation of either disulphide bonds or stronger S-H . . .O (or N) 'no rmal' hydrogen bonds in a protein environment. Interactions between the sid e chains of phenylalanine and cysteine residues are characterized as the ph enyl( Phe)-(HSCH2-)(Cys) interaction. The bonding energy for such interacti ons is approximately 3.71 kcal mol(-1) and is achieved in a geometric arran gement with an optimal phenyl(Phe)-(HS-)(Cys) pi -type hydrogen bonding int eraction. The interaction is very sensitive to the orientation of the two l one electron pairs on the sulphur atom relative to the p electron cloud of the phenyl ring. Accordingly, the interaction configurations that can accom plish a significant bonding energy exist only within a narrow configuration al space. The database analysis of 609 experimental X-ray protein structure s demonstrates that only 268 of the 1620 cysteine residues involve such phe nylalanine-cysteine side chain interactions. Most of these interactions occ ur in the form of pi (aromatic)-lone pair(sulphur) attractions, and corresp ond to a bonding energy less than 1.5 kcal mol(-1). A few were identified a s the aromatic-thiol hydrogen bond with a bonding energy of 2.0-3.6 kcal mo l(-1).