GRP78: A possible relationship of COVID-19 and the mucormycosis; in silico perspective

Abstract

Mucormycosis is a severe fungal infection reported in many cancer survivors, diabetic and immune-suppressed patients during organ transplants. A vast spark in the reported COVID-19 cases is noticed in India during the second wave in May 2021, when Mucormycosis is declared an epidemic. Despite being a rare disease, the mortality rate associated with Mucormycosis is more than 40%. Spore coat proteins (CotH) are essential proteins in many pathogenic bacteria and fungi. CotH3 was reported as the vital protein required for fungal virulence in Mucormycosis. We previously reported the involvement of the host cell-surface receptor GRP78 in SARS-CoV-2 spike recognition. Additionally, GRP78 is known to be the virulence factor during Mucormycosis. Using state-of-the-art structural bioinformatics and molecular modeling tools, we predicted the GRP78 binding site to the Rhizopus delemar CotH3 protein. Our findings pave the way toward rationally designing small molecule inhibitors targeting the GRP78 and its counter proteins in both pathogenic viral (SARS-CoV-2 spike) and fungal (R. delemar CotH3) diseases.

Keywords: COVID-19; CotH3; GRP78; Mucormycosis; Protein-protein docking; Spike.

Fig. 1

Multiple sequence alignment of eukaryotic protein kinase (EPK) (PDB: 1ATP), Fungal CotH3, and Bacterial CotH (PDB: 5JD9).

Fig. 2

A) The Ramachandran plot of the predicted model of CotH3 of Rhizopus delmar. B) The predicted average binding affinity of AMP to the fungal CotH3 (green) and the bacterial CotH (red) apo structure (PDB ID: 5JDA).

Fig. 3

The MDS analysis of the CotH3-AMP system during 120 ns. (A) The Root Mean Square Deviation (RMSD) in blue and the Radius of Gyration (RoG) in red, versus the simulation time (in nanoseconds). (B) H-bond occupancy versus time in ns. (C) The per-residue Root Mean Square Fluctuations (RMSF). Protein conformation is represented in colored cartoon representation according to the coloring scheme on the up-right corner.

Fig. 4

(A) The binding affinity of the CotH3 (blue column) and Spikes of SARS-CoV-2 (blue, cyan, and purple columns) against GRP78 calculated using HADDOCK software. (B) The docked complexes are superimposed on each other (left-hand side), and one of the formed complexes (right-hand side) shown in cartoon representation (top) and surface presentation (below) with 90° rotation on the x-axis. C) The formed interactions in (B) represented by PyMOL after the PLIP webserver run. The different interactions are depicted as per legend at the bottom of the figure.

Fig. 5

Molecular Dynamics Simulation (50 ns) of the GRP78-CotH3 complex after docking. (A) The Root Mean Square Deviation (RMSD) in blue, the Radius of Gyration (RoG) in orange, and the Surface Accessible Surface Area (SASA) in gray, versus the simulation time in nanoseconds. (B) The per-residue Root Mean Square Fluctuations (RMSF) of the GRP78-CotH3 complex (red), GRP78 (green) and CotH3 (blue). The interacting regions in both protein are enlarged for clarification.