Matrix metalloproteinase/Fas ligand (MMP/FasL) interaction dynamics in COVID-19: An in silico study and neuroimmune perspective

Background: and provide neuroimmune insights for future. Methods: We enrolled and analyzed a clinical cohort of COVID-19 patients, and recorded their blood Na + levels and temperature at admission. A blood-like molecular dynamics simulation (MDS) box was then built. Four conditions were studied; MMP7/FasL (healthy), MMP7/FasL (COVID-19), MMP9-FasL (healthy), and MMP9/FasL (COVID-19). MDS was performed by GROningen MAchine for Chemical Simulation (GROMACS). We analyzed bonds, short-range energies, and free binding energies to draw conclusions on the interaction of MMP7/MMP9 and FasL to gain insights into COVID-19 immunopathology. Genevestigator was used study RNA-seq/microarray expression data of MMPs in the cells of immune and nervous systems. Finally, epitopes of MMP/FasL complexes were identified as drug targets by machine learning (ML) tools. Results: MMP7-FasL (Healthy), MMP7-FasL (COVID-19), MMP9-FasL (Healthy), and MMP9-FasL (COVID-19) systems showed 0, 1, 4, and 2 salt bridges, indicating MMP9 had more salt bridges. Moreover, in both COVID-19 and normal conditions, the number of interacting residues and surface area was higher for MMP9 compared to MMP7 group. The COVID-19 MMP9-FasL group had more H-bonds compared to MMP7-FasL group (12 vs. 7). 15 epitopes for FasL-MMP9 and 10 epitopes for FasL-MMP7 were detected. Extended MD simulation for 100 ns confirmed stronger binding of MMP9 based on Molecular Mechanics Generalized Borne Surface analysis (MM-GBSA) and Coul and Leonard-Jones (LJ) short-range energies. Conclusions: MMP9 interacts stronger than MMP7 with FasL, however, both molecules maintained strong interaction through the MDS. We suggested epitopes for MMP-FasL complexes as valuable therapeutic targets in COVID-19. These data could be utilized in future immune drug and protein design and repurposing efforts.

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