An important target and focus of research with SARS-CoV-2 has been the virus’ spike protein, its binding to the host angiotensin-converting enzyme 2 (ACE2) protein and engaging an immune response to the spike protein for vaccine development. However, the virus produces other important proteins, such as ORF7a and ORF7b, and prior studies have demonstrated that these proteins localize to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). Furthermore, expression of both proteins is correlated with virulence <i>in vivo</i>; for ORF7a, a direct association with host bone marrow stromal antigen 2 (BST-2) suppresses its anti-viral activity, whereas for ORF7b, the ability to form homooligomers is suggested to be a key mechanism by which it can remain ERGIC associated. However, specific, structural models of these homo- and heterooligomeric interfaces are not known, nor are the key protein-protein interfaces for each. A multi-scale simulation approach has been used to study the dimerization of ORF7a with BST-2 and self-ORF7b. Monomers are separated in a simple membrane model and the MARTINI coarse-grained (CG) force field (FF) is used to simulate association of dimers and all-atom molecular dynamics (MD) is used to refine the CG structures. ORF7a has a bulky cytoplasmic (CYTO) domain that can potentially interact with the CYTO domain of BST-2. Our preliminary MD simulations suggest this CYTO interaction but also important transmembrane (TM) interaction that agrees with experimental assays from Dr. Bryan Berger’s lab at U. Virginia. For ORF7b, the orientation of this shorter (mainly TM peptide) is unknown and MD simulations have been performed with parallel and anti-parallel monomers. Each orientation shows dimerization but there exist stronger interactions with anti-parallel orientations with elevated π-π and π-amide interactions. Future experimental studies on ORF7b will probe details of the dimer interface and membrane orientation. The work presented here provides an initial understanding of these two accessory proteins that lays fundamentals towards future work in inhibition of dimer formation.

Accessory proteins of SARS-CoV-2: A study of the dimerization of ORF7a and ORF7b

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.