mOLECULAR ANALySIS OF THE INTERACTION BETWEEN STAPHyLOCOCCUS AUREUS PROTEIN SBI AND ImmUNE SySTEm PROTEIN C

Protein-protein interactions form the basis of cellular communication, signaling, and regulation. These interactions are governed by non-covalent forces, originating from electrostatic and van der Waals interactions at atomic resolution. Electrostatic interactions are often crucial to protein recognition and binding, particularly for highly and oppositely charged proteins. We examined the interactions between secreted protein Sbi from antibiotic-resistant strains of S. aureus with host immune system protein C3d, using electrostatic clustering and free energy analysis. We used the computational framework called Analysis of Electrostatic Similarities Of Proteins (AESOP) to perform computational alanine scans and we generated a series of protein variants with perturbed electrostatic properties. To elucidate the effect of each mutation in association (defined as recognition plus binding) of Sbi with C3d, we performed electrostatic clustering and association free energy calculations. The analysis of our data revealed which charged amino acids are important for the formation of the C3d-Sbi complex, thus pointing out gain-of-association or loss-of-association mutations. This knowledge will form the basis for the design of proteins with tailored binding properties, and thus tailored biological function, by incorporating multiple critical mutations. This project will guide the development of novel therapeutics for treatment of infections by S. aureus.