
@article {87089,
	title = {The molecular mechanism of domain-swapping of the C-terminal domain of the SARS coronavirus main protease},
	journal = {Biophys J},
	volume = {120},
	year = {2021},
	month = {12/2020},
	pages = {504-516},
	abstract = {<p>In 3D-domain-swapping, two protein monomers exchange a part of their structures to form an intertwined homodimer, whose subunits resemble the monomer. Several viral proteins domain-swap to increase their structural complexity or functional avidity. The main protease (M<sup>pro</sup>) of the SARS coronavirus proteolyzes viral polyproteins and has been a target for anti-SARS drug design. Domain-swapping in the α-helical C-terminal domain of M<sup>pro</sup> (M<sup>pro</sup>C) locks M<sup>pro</sup> into a hyperactive octameric form which is hypothesized to promote the early stages of viral replication. However, in the absence of a complete molecular understanding of the mechanism of domain-swapping, investigations into the biological relevance of this octameric M<sup>pro</sup> have stalled. Isolated M<sup>pro</sup>C can exist as a monomer or a domain-swapped dimer. Here, we investigate the mechanism of domain-swapping of M<sup>pro</sup>C using coarse-grained structure-based models and molecular dynamics simulations. Our simulations recapitulate several experimental features of M<sup>pro</sup>C folding. Further, we find that a contact between a tryptophan in the M<sup>pro</sup>C domain-swapping hinge and an arginine elsewhere forms early during folding, modulates the folding route and promotes domain-swapping to the native structure. An examination of the sequence and the structure of the tryptophan containing hinge loop shows that it has a propensity to form multiple secondary structures and contacts, indicating that it could be stabilized into either the monomer- or dimer-promoting conformations by mutations or ligand binding. Finally, since all residues in the tryptophan loop are identical in SARS-CoV and SARS-CoV-2, mutations that modulate domain-swapping may provide insights into the role of octameric M<sup>pro</sup> in the early stage viral replication of both viruses.</p>
},
	doi = {10.1016/j.bpj.2020.11.2277},
	author = {Terse, VL and Gosavi, S}
}
