Law Cheh Tat, Camacho Frank, Garcia-Alles Luis F, Gilleron Martine, Sarmiento Maria E, Norazmi Mohd Nor, Acosta Armando, Choong Yee Siew
Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Minden, Malaysia.
Biologicals Sciences School, University of Conception, Chile.
Tuberculosis (Edinb). 2019 Jan;114:9-16. doi: 10.1016/j.tube.2018.11.002. Epub 2018 Nov 4.
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 (AcSGL) had been previously developed. In order to study the interactions of dAbk11 with AcSGL:CD1b, the conformation of AcSGL within CD1b was first modelled. The orientation of dAbκ11 with AcSGL:CD1b was then predicted by a docking experiment and the complex was sampled using molecular dynamics simulation. Data showed that dAbκ11 Tyr32 O plays a decisive role in interacting with AcSGL alkyl tail H. The binding free energy calculation showed that AcSGL establish strong hydrophobic interactions with dAbκ11. The model also predicted a higher affinity for the natural sulfoglycolipid (AcSGL) than the synthetic analogue (SGL12), which was supported by the ELISA data. These results shed light on the likely mechanism of interactions between AcSGL:CD1b and dAbκ11, thus making possible to envision the strategies for dAbκ11 optimization for possible future applications.
结核病（TB）是所有传染病中导致死亡的主要原因。CD1b分子呈递脂质以及CD1b-脂质复合物与免疫受体的相互作用对于理解对结核分枝杆菌（Mtb）的免疫反应以及开发结核病控制方法至关重要。先前已开发出一种识别CD1b与Mtb硫糖脂（AcSGL）复合物的特异性结构域抗体（dAbk11）。为了研究dAbk11与AcSGL:CD1b的相互作用，首先对CD1b内AcSGL的构象进行了建模。然后通过对接实验预测dAbκ11与AcSGL:CD1b的取向，并使用分子动力学模拟对该复合物进行采样。数据表明，dAbκ11的Tyr32 O在与AcSGL烷基尾H相互作用中起决定性作用。结合自由能计算表明，AcSGL与dAbκ11建立了强烈的疏水相互作用。该模型还预测，与合成类似物（SGL12）相比，对天然硫糖脂（AcSGL）具有更高的亲和力，这得到了ELISA数据的支持。这些结果揭示了AcSGL:CD1b与dAbκ11之间相互作用的可能机制，从而使得设想dAbκ11优化策略以用于未来可能的应用成为可能。
