Elucidation of SARS-Cov-2 Budding Mechanisms through Molecular Dynamics Simulations of M and E Protein Complexes

Collins, Logan Thrasher; Elkholy, Tamer; Mubin, Shafat; Hill, David E.; Williams, Ricky; Ezike, Kayode; Singhal, Ankush

doi:10.1021/acs.jpclett.1c02955

Cited by 22 publications

(17 citation statements)

References 35 publications

(78 reference statements)

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“…Despite the M protein dimer being crucial for various biological functions such as SARS-CoV-2 virion assembly and shape formation [ 63 ], the type of interactions established in its homodimer form are still poorly understood [ 9 , 12 ]. Experimental SARS-CoV M protein dimer data demonstrated that residues W19, W57, P58, W91, L92, Y94, F95, and C158 were relevant, suggesting that homologous residues W20 (TMH1 domain), W58, and P59 (TMH2 domain), and W92, L93 Y95, and F96 (TMH3 domain) of SARS-CoV-2 may also be important for M dimer interaction and stabilization [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

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

Marques-Pereira

Pires

Gouveia

et al. 2022

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

“…As such, this region seems to be the best candidate area for the development of a new drug/peptide to inhibit SARS-CoV-2 M protein dimer formation. This zone was also a promising target in another approach that searched for druggable targets in the homodimeric structure [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

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

Marques-Pereira

Pires

Gouveia

et al. 2022

IJMS

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“…All-atom molecular dynamics simulations provide powerful analytic tools in analyzing protein–protein interactions. However, because these processes represent miniscule portions of an immensely larger enterprise and occur over time scales on the order of nanoseconds, they are nearly impossible to apply to the entire assembly and budding process [ 30 , 31 , 32 ]. To this end, coarse-grained (CG) modeling has been employed to explore the kinetics of assembly of spherical icosahedral viruses.…”

Section: Introductionmentioning

confidence: 99%

Biophysical Modeling of SARS-CoV-2 Assembly: Genome Condensation and Budding

Zandi

2022

Viruses

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The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spurred unprecedented and concerted worldwide research to curtail and eradicate this pathogen. SARS-CoV-2 has four structural proteins: Envelope (E), Membrane (M), Nucleocapsid (N), and Spike (S), which self-assemble along with its RNA into the infectious virus by budding from intracellular lipid membranes. In this paper, we develop a model to explore the mechanisms of RNA condensation by structural proteins, protein oligomerization and cellular membrane–protein interactions that control the budding process and the ultimate virus structure. Using molecular dynamics simulations, we have deciphered how the positively charged N proteins interact and condense the very long genomic RNA resulting in its packaging by a lipid envelope decorated with structure proteins inside a host cell. Furthermore, considering the length of RNA and the size of the virus, we find that the intrinsic curvature of M proteins is essential for virus budding. While most current research has focused on the S protein, which is responsible for viral entry, and it has been motivated by the need to develop efficacious vaccines, the development of resistance through mutations in this crucial protein makes it essential to elucidate the details of the viral life cycle to identify other drug targets for future therapy. Our simulations will provide insight into the viral life cycle through the assembly of viral particles de novo and potentially identify therapeutic targets for future drug development.

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“…These results are in agreement with Kuzmin et al‘s work, where the authors found that the induction of membrane curvature by the E protein led to thinner membrane close to the TM regions but thicker around the CTDs ( Kuzmin et al, 2022 ). Yet, another study by Collins et al found that the E protein was not able to facilitate membrane curvature ( Collins et al, 2021 ). These inconsistent results might arise from the different protein structural models (Heo and Feig’s predicted model ( Heo and Feig, 2020 ) vs. our refined model generated from MD simulations) or the different membrane systems used in the studies (ERGIC mimic vs. pure POPC).…”

Section: Resultsmentioning

confidence: 99%

Refinement of SARS-CoV-2 envelope protein structure in a native-like environment by molecular dynamics simulations

Wang

Rubino

et al. 2022

Front. Mol. Biosci.

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COVID-19 has become an unprecedented threat to human health. The SARS-CoV-2 envelope (E) protein plays a critical role in the viral maturation process and pathogenesis. Despite intensive investigation, its structure in physiological conditions remains mysterious: no high-resolution full-length structure is available and only an NMR structure of the transmembrane (TM) region has been determined. Here, we present a refined E protein structure, using molecular dynamics (MD) simulations to investigate its structure and dynamics in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer system. Our initial homology model based upon the SARS-CoV E protein structure is shown to be unstable in the lipid bilayer, and the H3 helices tend to move away from the membrane center to the membrane-water interface. A more stable model was developed by replacing all H3 helices with the fully equilibrated H3 structure sampled in the MD simulations. This refined model exhibited more favorable contacts with lipids and water than the original homology model and induced local membrane curvature, decreasing local lipid order. Interestingly, the pore radius profiles showed that the channel in both homology and refined models remained in a closed state throughout the simulations. We also demonstrated the utility of this structure to develop anti-SARS-CoV-2 drugs by docking a library of FDA-approved, investigational, and experimental drugs to the refined E protein structure, identifying 20 potential channel blockers. This highlights the power of MD simulations to refine low-resolution structures of membrane proteins in a native-like membrane environment, shedding light on the structural features of the E protein and providing a platform for the development of novel antiviral treatments.

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Elucidation of SARS-Cov-2 Budding Mechanisms through Molecular Dynamics Simulations of M and E Protein Complexes

Cited by 22 publications

References 35 publications

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

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

Biophysical Modeling of SARS-CoV-2 Assembly: Genome Condensation and Budding

Refinement of SARS-CoV-2 envelope protein structure in a native-like environment by molecular dynamics simulations

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