Karnchanapandh Kun, Hanpaibool Chonnikan, Sanachai Kamonpan, Rungrotmongkol Thanyada
Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand.
Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
J Biomol Struct Dyn. 2024 Feb-Mar;42(4):1617-1628. doi: 10.1080/07391102.2023.2201360. Epub 2023 Apr 26.
or infection (CDI) is currently one of the major causes of epidemics worldwide. Toxin B from toxin B (TcdB) infection is the main target protein inhibiting CDI recurrence. Clinical research suggested that bezlotoxumab's (Bez) efficiency is significantly reduced in neutralizing the B2 strain compared to the B1 strain. The monoclonal antibody (mAb) functions by binding to the epitope 1 and 2 regions in the combined repetitive oligopeptide (CROP) domain. Some binding residues are distinctively different between B1 and B2 strains. In this work, we aimed to elucidate and compare insights into the interaction of toxins B1 and B2 in complex with Bez by using all-atom molecular dynamics (MD) simulations and binding free energy calculations. The predicted Δ values suggested that the antibody (Ab) could bind to toxin B1 significantly better than B2, supported by higher salt bridge and hydrogen bonding (H-bonding) interactions, as well as the number of contact residues between the two focused proteins. The toxin B1 residues important for binding with Bez were E1878, T1901, E1902, F1905, N1941, V1946, N2031, T2032, E2033, V2076, V2077, and E2092. The lower susceptibility of Bez towards toxin B2 was primarily due to a change of residue E2033 from glutamate to alanine (A2033) and the loss of E1878 and E1902 contributions, as determined by the intermolecular interaction changes from the dynamic residue interaction network (dRIN) analysis. The obtained data strengthen our understanding of Bez/toxin B binding.
艰难梭菌感染（CDI）是当前全球流行的主要原因之一。来自艰难梭菌毒素B（TcdB）感染的毒素B是抑制CDI复发的主要靶蛋白。临床研究表明，与B1菌株相比，bezlotoxumab（Bez）中和B2菌株的效率显著降低。单克隆抗体（mAb）通过与组合重复寡肽（CROP）结构域中的表位1和2区域结合发挥作用。B1和B2菌株之间的一些结合残基明显不同。在这项工作中，我们旨在通过全原子分子动力学（MD）模拟和结合自由能计算，阐明并比较毒素B1和B2与Bez复合物相互作用的见解。预测的Δ值表明，抗体（Ab）与毒素B1的结合明显优于B2，这得到了更高的盐桥和氢键（H键）相互作用以及两种目标蛋白之间接触残基数量的支持。与Bez结合重要的毒素B1残基为E1878、T1901、E1902、F1905、N1941、V1946、N2031、T2032、E2033、V2076、V2077和E2092。Bez对毒素B2敏感性较低的主要原因是，通过动态残基相互作用网络（dRIN）分析确定，残基E2033从谷氨酸变为丙氨酸（A2033），以及E1878和E1902贡献的丧失。所获得的数据加深了我们对Bez/毒素B结合的理解。
