Probing the formation, structure and free energy relationships of M protein dimers of SARS-CoV-2

Yipeng Cao; Rui Yang; Wei Wang; Shengpeng Jiang; Chengwen Yang; Ningbo Liu; Hongji Dai; Imshik Lee; Xiangfei Meng; Zhiyong Yuan

doi:10.1016/j.csbj.2022.01.007

Probing the formation, structure and free energy relationships of M protein dimers of SARS-CoV-2

Comput Struct Biotechnol J. 2022 Jan 11:20:573-582. doi: 10.1016/j.csbj.2022.01.007. eCollection 2022.

Authors

Yipeng Cao^{1

2}, Rui Yang³, Wei Wang¹, Shengpeng Jiang¹, Chengwen Yang¹, Ningbo Liu¹, Hongji Dai^{1

4}, Imshik Lee⁵, Xiangfei Meng², Zhiyong Yuan¹

Affiliations

¹ Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060 PR China.
² National Supercomputer Center in Tianjin, 300457 PR China.
³ Department of Infection and Immunity, Tianjin Union Medical Center, Nankai University Affiliated Hospital. 300031, PR China.
⁴ College of Physics, Nankai University, Tianjin 300071, PR China.
⁵ Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, PR China.

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 residues; COVID-19; Coronavirus; Dimer function; Free energy calculations; MMPBSA; Membrane (M) protein; Molecular dynamic simulations; PMF; SARS-CoV-2.