Li Jiao, Zhang Hao, Liu Ning, Ma Yi Bo, Wang Wei Bu, Li Qi Ming, Su Ji Guo
High Performance Computing Center, National Vaccine and Serum Institute (NVSI), Beijing101111, China.
National Engineering Center for New Vaccine Research, Beijing101111, China.
ACS Omega. 2022 Dec 16;8(1):782-790. doi: 10.1021/acsomega.2c06114. eCollection 2023 Jan 10.
Poliovirus (PV) is an infectious virus that causes poliomyelitis, which seriously threatens the health of children. The release of viral RNA is a key step of PV in host cell infection, and multiple lines of evidence have demonstrated that RNA release is initiated by the opening of the twofold channels of the PV capsid. However, the mechanism that controls the twofold channel opening is still not well understood. In addition, the channel opening motion of the recombinant PV capsid leads to the destruction of predominant neutralizing epitopes and thus hinders the capsid as a vaccine immunogen. Therefore, it is important to identify the intrinsic motions and the related key residues controlling the twofold channel opening for understanding the virus infection mechanism and developing capsid-based vaccines. In the present work, the width of the channel was selected as an internal coordinate directly related to the channel opening, and then the elastic network model (ENM) combined with the group theory were employed to extract the intrinsic motion modes that mostly contribute to the opening of the twofold channels. Our results show that the channel opening predominately induced by the breathing motion and the overall rotation of each protomer in the capsid. Then, an internal coordinate-based perturbation method was used to identify the key residues regulating the twofold channel opening of PV. The calculation results showed that the predicted key residues are mainly located at the twofold axes, the bottom of the canyons and the quasi threefold axes. Our study is helpful for better understanding the twofold channel opening mechanism and provides a potential target for preventing the opening of the channels, which is of great significance for PV vaccine design. The source code of this study is available at https://github.com/SJGLAB/CapsidKeyRes.git.
脊髓灰质炎病毒（PV）是一种引发小儿麻痹症的传染性病毒，严重威胁儿童健康。病毒RNA的释放是PV感染宿主细胞的关键步骤，多项证据表明RNA释放是由PV衣壳双重通道的打开引发的。然而，控制双重通道打开的机制仍未得到充分理解。此外，重组PV衣壳的通道打开运动会导致主要中和表位的破坏，从而阻碍衣壳作为疫苗免疫原。因此，识别控制双重通道打开的内在运动和相关关键残基对于理解病毒感染机制和开发基于衣壳的疫苗至关重要。在本研究中，选择通道宽度作为与通道打开直接相关的内部坐标，然后采用弹性网络模型（ENM）结合群论来提取对双重通道打开贡献最大的内在运动模式。我们的结果表明，通道打开主要由衣壳中每个原体的呼吸运动和整体旋转诱导。然后，使用基于内部坐标的微扰方法来识别调节PV双重通道打开的关键残基。计算结果表明，预测的关键残基主要位于双重轴、峡谷底部和准三重轴处。我们的研究有助于更好地理解双重通道打开机制，并为阻止通道打开提供了潜在靶点，这对PV疫苗设计具有重要意义。本研究的源代码可在https://github.com/SJGLAB/CapsidKeyRes.git获取。
