Interactions of domain antibody (dAbκ11) with Mycobacterium tuberculosis Ac2SGL in complex with CD1b

Abstract

Tuberculosis (TB) is the main cause of mortality among all infectious diseases. The presentation of lipids by CD1b molecules and the interactions of the CD1b-lipid complexes with the immune receptors are important for the understanding of the immune response to Mycobacterium tuberculosis (Mtb), and to develop TB control methods. A specific domain antibody (dAbk11) recognizing the complex of CD1b with Mtb sulphoglycolipid (Ac₂SGL) had been previously developed. In order to study the interactions of dAbk11 with Ac₂SGL:CD1b, the conformation of Ac₂SGL within CD1b was first modelled. The orientation of dAbκ11 with Ac₂SGL:CD1b was then predicted by a docking experiment and the complex was sampled using molecular dynamics simulation. Data showed that dAbκ11 Tyr32 O_H plays a decisive role in interacting with Ac₂SGL alkyl tail H_O17. The binding free energy calculation showed that Ac₂SGL establish strong hydrophobic interactions with dAbκ11. The model also predicted a higher affinity for the natural sulfoglycolipid (Ac₂SGL) than the synthetic analogue (SGL12), which was supported by the ELISA data. These results shed light on the likely mechanism of interactions between Ac₂SGL:CD1b and dAbκ11, thus making possible to envision the strategies for dAbκ11 optimization for possible future applications.

Keywords: Ac(2)SGL; Binding free energy; Mycobacterium tuberculosis; Single domain antibody dAbκ11; Socking and molecular dynamics (MD) simulation.