Molecular dynamics of human-specific cytolysin: analysis of membrane binding motif for therapeutic application.

BACKGROUND Intermedilysin (ILY) is a human-specific cytolysin secreted from Streptococcus intermedius. In this study, the dynamic structure of ILY, StreptolysinO (SLO) and their 12mer substituted mutants for 500 ps was analyzed. Several parameters, such as dipole moment and electrostatic potential, were determined to elucidate the molecular mechanism of membrane binding. MATERIALS AND METHODS Molecular models of lLY, SLO and their mutants were constructed using Insightll-Discover with the Homology module. Their molecular dynamics were simulated with the Discover3 (Insight module), and z-matrix data of the membrane-binding 12mer region were extracted to calculate the molecular orbital (MO) parameters (i.e., dipole moment, solvation free energy (dGW)). RESULTS Cytolysins vibrated like a bow, and the dipole moment direction of ILY 12mer region was different from that of SLO. Certain ILY mutants indicated the SLO-like dipole properties, which had an SLO-type limer cysteine motif amino acid sequence. The ILY 11mer region was more hydrophobic than that of SLO, and seemed to interact easily with the cell membrane without cholesterol. The electrostatic potential field distribution of ILY differed from that of SLO, especially in the 11mer region. CONCLUSION In the 11mer region, the dipole moment directions of these cytolysins were constant during molecular movement, and ready to interact with membrane components (i.e., cholesterol, phospholipid).