Understanding the association of cell-surface proteins (ACE2 and GRP78) facilitating pathogen recognition: a computational approach.

Angiotensin-converting enzyme 2 (ACE2) has been reported to be the primary host cell receptor for recognizing SARS-CoV and SARS-CoV-2 spike proteins. This host-cell element, despite having a crucial role in normal cells, may be hijacked by viruses to invade human cells. It has been reported that ACE2 trafficking to the cell membrane is mediated by other cellular factors, such as the endoplasmic reticulum resident chaperone, named glucose-regulated protein 78 (GRP78). GRP78 is the master of the unfolded protein response during cellular stress. This study uses sequence alignment, protein-protein docking, and molecular dynamics simulation (MDS) to predict the potential binding sites between the two proteins for the first time aiming to understand its role in viral recognition and infection. Results revealed three critical regions in ACE2 (C133-C141, C344-C361, and C530-C542), that could be the recognition site for GRP78 from which, the second region (C344-C361) is the suggested best region based on protein-protein docking, MDS, and MM-GBSA calculations. These cyclic regions show similarity (<38% identity) with the cyclic peptide Pep42, which is previously reported to target GRP78 over cancer cells. This approach paves the way toward suggesting potential inhibitors based on the prevention of the association between ACE2 and GRP78.