Theoretical insight into sulfur–aromatic interactions with extension to D2 receptor activation mechanism

Abstract

Contacts between aromatic rings and sulfur-containing amino acids are frequent in proteins. However, little is known about the nature of their interactions particularly if substituents are present on aromatic ring. In this paper, DFT quantum chemical calculations were used to study substituted benzenes in complex with hydrogen sulfide (H2S), methanethiol (CH3SH), and (Methylsulfanyl)methane (CH3SCH3). It was found that SH···π interaction is more stabilizing than the S···π interaction in the case of benzene, but this is changed with increasing electronegativity of the substituent on benzene ring. Although the change of energy of SH···π and S···π interaction follows the conventional model of substituent effect, where S···π interactions are maximized and SH···π interactions are diminished with electron-withdrawing substituent on benzene as a result of changes in the aryl π-system, it was found that it is mainly a consequence of direct electrostatic interaction between substituent and the sulfur-containing molecule. We also investigated the model system of Cys···Trp interaction, adjacent to a cluster of aromatic amino acids, in proteins, using explicit membrane molecular dynamics simulations results of D3 dopamine receptor crystal structure as starting point. It was found that fluorination in aromatic cluster enhances the Cys···Trp interaction. The effect is maximized when transferred through the rest of aromatic system suggesting possible explanation for frequent contacts between sulfur-containing and aromatic amino acids in proteins and their effects on protein folding and stabilization.