Probing the flexibility of Zika virus envelope protein DIII epitopes using molecular dynamics simulations

Zika virus (ZIKV) envelope protein (E) domain III (DIII) mediates viral attachment and fusion. The DIII facilitates cell receptor recognition, and includes several ZIKV antibody epitopes. The DIII is also considered as an antigenic target for ZIKV-neutralising antibodies. Understanding the flexibility and dynamical behaviour of ZIKV DIII can aid the design of vaccines against ZIKV. Using molecular dynamics (MD) simulations, the flexibility of DIII and its epitopes were characterised. The final structure from a 100 ns-long MD simulation was docked to anti-DIII ZIKV Fabs (ZV67 and ZV64). Interestingly, the analysis of the MD simulations revealed that the residues of the C-C’ loop and the ABDE sheet epitopes (epitopes for moderately neutralising ZV64 and weakly neutralising ZV2 mAbs, respectively) were highly flexible, whereas the LR epitope for strongly neutralising ZV67 mAb was rigid.寨卡病毒（Zika virus, ZIKV）包膜蛋白（envelope protein, E）结构域III（domain III, DIII）可介导病毒附着与融合过程。该结构域能够介导细胞受体识别，并包含多个寨卡病毒抗体表位，同时也被视为寨卡病毒中和抗体的抗原靶点。解析寨卡病毒DIII的柔性与动态行为，有助于寨卡病毒疫苗的研发设计。本研究通过分子动力学（molecular dynamics, MD）模拟，对DIII及其表位的柔性特征进行了表征；将100纳秒时长MD模拟得到的最终结构，与抗DIII寨卡病毒抗原结合片段（Fabs）ZV67及ZV64进行分子对接。有趣的是，MD模拟分析结果显示，C-C'环与ABDE折叠片层表位（分别对应中度中和性单克隆抗体ZV64与弱中和性单克隆抗体ZV2的表位）的氨基酸残基具有较高柔性；而针对强中和性单克隆抗体ZV67的LR表位则呈现刚性特征。