Key result
G49V mutation increases ORF3a helix Young's modulus ~29% versus wild-type in molecular simulations.
Why the study?
Further research was needed to complete the knowledge of SARS-CoV-2 ORF3a and clarify its leading role in coronavirus functioning by investigating its mechanical properties and structural dynamics under physical stimuli.
Absolute Event Rate: 2.08% vs 1.61%
Molecular dynamics simulations reveal that the G49V mutation in the SARS-CoV-2 ORF3a protein increases its mechanical stability, which may inform the development of novel nanovalves or antiviral strategies.
Simulation data on ORF3a stability remain hypothesis-generating; leaves open any antiviral or nanovalve applications pending experimental validation.
SARS-CoV-2-encoded accessory protein ORF3a was found to be a conserved coronavirus protein that shows crucial roles in apoptosis in cells as well as in virus release and replications. To complete the knowledge and identify the unknown of this protein, further comprehensive research is needed to clarify the leading role of ORF3a in the functioning of the coronavirus. One of the efficient approaches to determining the functionality of this protein is to investigate the mechanical properties and study its structural dynamics in the presence of physical stimuli. Herein, performing all-atom steered molecular dynamics (SMD) simulations, the mechanical properties of the force-bearing components of the ORF3a channel are calculated in different physiological conditions. As variations occurring in ORF3a may lead to alteration in protein structure and function, the G49V mutation was also simulated to clarify the relationship between the mechanical properties and chemical stability of the protein by comparing the behavior of the wild-type and mutant Orf3a. From a physiological conditions point of view, it was observed that in the solvated system, the presence of water molecules reduces Young's modulus of TM1 by ∼30 %. Our results also show that by substitution of Gly49 with valine, Young's modulus of the whole helix increases from 1.61 ± 0.20 to 2.08 ± 0.15 GPa, which is consistent with the calculated difference in free energy of wild-type and mutant helices. In addition to finding a way to fight against Covid-19 disease, understanding the mechanical behavior of these biological nanochannels can lead to the development of the potential applications of the ORF3a protein channel, such as tunable nanovalves in smart drug delivery systems, nanofilters in the new generation of desalination systems, and promising applications in DNA sequencing.
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Maymand et al. (2023) studied SARS-CoV-2. G49V mutation vs. Wild-type Orf3a was evaluated on Young's modulus of the whole helix. In steered molecular dynamics simulations, the G49V mutation increased Young's modulus of the ORF3a helix from 1.61 ± 0.20 GPa to 2.08 ± 0.15 GPa compared to wild-type.
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