SARS-CoV-2 Membrane Protein: From Genomic Data to Structural New Insights

Abstract

Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) is composed of four structural proteins and several accessory non-structural proteins. SARS-CoV-2’s most abundant structural protein, Membrane (M) protein, has a pivotal role both during viral infection cycle and host interferon antagonism. This is a highly conserved viral protein, thus an interesting and suitable target for drug discovery. In this paper, we explain the structural nature of M protein homodimer. To do so, we developed and applied a detailed and robust in silico workflow to predict M protein dimeric structure, membrane orientation, and interface characterization. Single Nucleotide Polymorphisms (SNPs) in M protein were retrieved from over 1.2 M SARS-CoV-2 genomes and proteins from the Global Initiative on Sharing All Influenza Data (GISAID) database, 91 of which were located at the predicted dimer interface. Among those, we identified SNPs in Variants of Concern (VOC) and Variants of Interest (VOI). Binding free energy differences were evaluated for dimer interfacial SNPs to infer mutant protein stabilities. A few high-prevalent mutated residues were found to be especially relevant in VOC and VOI. This realization may be a game-changer to structure-driven formulation of new therapeutics for SARS-CoV-2.

Molecular Evolution of SARS-CoV-2 during the COVID-19 Pandemic

“…In the same gene, a PSS associated with the L5F mutation facilitated the folding, assembly, and secretion of the virus [20], and PSSs associated with the mutations K417T, E484K, and L18F (also the N501Y mutation [133,134]) allowed escape from monoclonal antibodies [135][136][137][138]. Indeed, other detected PSSs were associated with the P681H mutation that increased the cleavage of spike protein with ACE2 [139] and the I82T mutation that increased the stability of the protein M [140]. In the gene ORF3a, a PSS associated with the Q57H mutation increased the affinity between the proteins ORF3a, spike, and M, favoring viral replication [141,142].…”

Conventional Understanding of SARS‐CoV‐2 Mpro and Common Strategies for Developing Its Inhibitors

“…It is the most widely distributed and consists of three parts: an extramembrane domain, three transmembrane domains, and an intramembrane domain. M protein is mainly responsible for assembly of the coronavirus envelope [23] . E protein has a molecular weight of 8.4–12 kDa and may aid in the assembly and release of viral particles [24–26] .…”

“…M protein is mainly responsible for assembly of the coronavirus envelope. [23] E protein has a molecular weight of 8.4-12 kDa and may aid in the assembly and release of viral particles. [24][25][26] The molecular weight of the N protein is 45.5 kDa and it can create a beaded structure with the virus's RNA to shield the viral genome from harm.…”

SARS-CoV-2 and the DNA damage response

“…The SARS-CoV-2 membrane protein (M) is the most abundant structural protein and is important for virus assembly and determining virus morphology and membrane budding [107][108][109][110][111]. M protein localizes in the endoplasmic reticulum Golgi intermediate compartment (ERGIC) and is essential for the recruitment of other viral proteins (see Table 1 for a summary of the subcellular distribution of SARS-CoV-2 proteins).…”