Comput Struct Biotechnol J . Probing the Formation, Structure and Free Energy Relationships of M Protein Dimers of SARS-CoV-2

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Comput Struct Biotechnol J


. 2022 Jan 11.
doi: 10.1016/j.csbj.2022.01.007. Online ahead of print.
Probing the Formation, Structure and Free Energy Relationships of M Protein Dimers of SARS-CoV-2


Yipeng Cao ^{1 2} , Rui Yang ³ , Wei Wang ¹ , Shengpeng Jiang ¹ , Chengwen Yang ¹ , Ningbo Liu ¹ , Hongji Dai ^{1 4} , Imshik Lee ⁵ , Xiangfei Meng ² , Zhiyong Yuan ¹



Affiliations

• PMID: 35047128
• PMCID: PMC8756865
• DOI: 10.1016/j.csbj.2022.01.007

Abstract

The M protein of the novel coronavirus 2019 (SARS-CoV-2) is the major structural component of the viral envelope and is also the minimum requirement for virus particle budding. M proteins generally exist as dimers. In virus assembly, they are the main driving force for envelope formation through lateral interactions and interactions with other viral structural proteins that play a central role. We built 100 candidate models and finally analyzed the six most convincing structural features of the SARS-CoV-2 M protein dimer based on long-timescale molecular dynamics (MD) simulations, multiple free energy analyses (potential mean force (PMF) and molecular mechanics Poisson-Boltzmann surface area (MMPBSA)) and principal component analysis (PCA) to obtain the most reasonable structure. The dimer stability was found to depend on the Leu-Ile zipper motif and aromatic amino acids in the transmembrane domain (TMD). Furthermore, the C-terminal domain (CTD) effects were relatively small. These results highlight a model in which there is sufficient binding affinity between the TMDs of M proteins to form dimers through the residues at the interface of the three transmembrane helices (TMHs). This study aims to help find more effective inhibitors of SARS-CoV-2 M dimers and to develop vaccines based on structural information.

Keywords: Binding free energy; COVID-19; Dimer; MD simulations; MMPBSA; Membrane (M) protein; PMF; SARS-CoV-2.