Self-association process of tetracycline antibiotic in different aqueous solutions: a joint experimental study and molecular dynamics simulation

Tetracycline is one of the most commonly used antibiotics in a wide range of antibacterial drugs. Self-association of drugs (e.g. antibiotics) causes problems, such as increasing toxicity and reducing penetration of drugs through cell membranes. In this study, the self-association process of tetracycline was investigated experimentally and theoretically in aqueous, ethanol, and salt solutions. Spectroscopy studies showed that the self-association process occurred in salt solution at lower concentrations of tetracycline in comparison with the other two solutions. However, the presence of ethanol led to a delay in the self-association process. The self-association constants of tetracycline were obtained by using experimental values. Moreover, the analysis of the number of clusters and solvent accessible surface area were carried out by molecular dynamics (MD) simulations. The MD results clarified that the tetracycline self-association process happened earlier in salt solution compared to the others through forming the larger clusters by the hydrophobic interactions, whereas the presence of ethanol caused a reduction in the self-association process and the cluster populations through weakening the hydrophobic interactions. Furthermore, the type of the involved interactions in the formation of the tetracycline clusters was investigated by RDG analysis. The obtained results revealed that van der Waals interactions possessed a fundamental influence on the formation of tetracycline clusters.