Conformational dynamics of the membrane protein of MERS-CoV in comparison with SARS-CoV-2 in ERGIC complex

The present study explores the conformational dynamics of the membrane protein of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) within the Endoplasmic Reticulum-Golgi Intermediate Compartment (ERGIC) complex using an all-atomistic molecular dynamics simulation approach. Significant structural changes were observed in the N-terminal, C-terminal, transmembrane, and beta-sheet sandwich domains of the MERS-CoV membrane protein. This study also highlights the structural similarities between the MERS-CoV and the SARS-CoV-2 membrane proteins, particularly in how both exhibit a distinct kink in the transmembrane helix caused by aromatic residue-lipid interactions. A structural expansion below the transmembrane and above the beta-sheet sandwich domain within the dimer was observed in all the M-proteins. This site on the beta-sheet sandwich domains near the C-terminal end could serve as a potential drug-binding site. Notably, a stable helical structure was identified in the C-terminal domain of the MERS-CoV membrane protein, whereas a proper secondary structural conformation was not observed in the SARS-CoV-2 membrane protein. Further, the SARS-CoV-2 membrane protein exhibited stronger binding to the lipid bilayer than the MERS-CoV, indicating its greater structural stability within the ERGIC complex. The structural similarity between the membrane protein of MERS-CoV and SARS-CoV-2 suggests the feasibility of employing a common inhibitor against these beta-coronaviruses. Furthermore, this analysis enhances our understanding of the membrane protein’s interactions with proteins and lipids, paving the way for therapeutic developments against these viruses.

本研究采用全原子分子动力学模拟（all-atomistic molecular dynamics simulation）方法，探究了中东呼吸综合征冠状病毒（Middle East Respiratory Syndrome Coronavirus, MERS-CoV）膜蛋白在内质网-高尔基体中间区室（Endoplasmic Reticulum-Golgi Intermediate Compartment, ERGIC）复合物中的构象动态变化。研究观察到，MERS-CoV膜蛋白的N端、C端、跨膜结构域及β折叠夹心结构域均发生了显著结构变化。本研究同时揭示了MERS-CoV与SARS-CoV-2膜蛋白之间的结构相似性：二者均因芳香族残基-脂质相互作用（aromatic residue-lipid interactions）在跨膜螺旋处形成独特的扭结结构。在所有冠状病毒膜蛋白的二聚体中，跨膜结构域下方、β折叠夹心结构域上方的区域均出现了结构扩张现象。该位于β折叠夹心结构域近C端的位点，可作为潜在的药物结合位点（drug-binding site）。值得注意的是，MERS-CoV膜蛋白的C端结构域中存在稳定的螺旋结构，而SARS-CoV-2膜蛋白则未观测到完整的二级结构构象（secondary structural conformation）。进一步研究表明，SARS-CoV-2膜蛋白与脂质双层（lipid bilayer）的结合强度高于MERS-CoV，这提示其在ERGIC复合物中具有更高的结构稳定性。MERS-CoV与SARS-CoV-2膜蛋白的结构相似性，证明开发针对这类β冠状病毒的通用抑制剂具备可行性。此外，本分析深化了我们对膜蛋白与蛋白质、脂质相互作用的认知，为针对这类病毒的治疗药物开发铺平了道路。