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Matrix metalloproteinase/Fas ligand (MMP/FasL) interaction dynamics in COVID-19: An in silico study and neuroimmune
Kiarash Saleki1,2,3,4, Cena Aram5, Parsa Alijanizadeh1,3
1Student Research Committee, Babol University of Medical Sciences, Babol, Iran.
Background:
The initiator of cytokine storm in Coronavirus disease (COVID-19) is still unknown. We recently suggested a complex interaction of matrix metalloproteinases (MMPs), Fas ligand (FasL), and viral entry factors could be responsible for the cytokine outrage In COVID-19. We explored the molecular dynamics of FasL/MMP7-9 in COVID-19 conditions in silico 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.
Insights
Matrix metalloproteinase-9 (MMP9) shows stronger binding with Fas ligand (FasL) than MMP7 in COVID-19 conditions. Identified MMP-FasL epitopes offer potential therapeutic targets for COVID-19 treatment.
Area of Science:
- Immunology
- Computational Biology
- Biochemistry
Background:
- The precise trigger for cytokine storm in COVID-19 remains unclear.
- A potential mechanism involves matrix metalloproteinases (MMPs), Fas ligand (FasL), and viral entry factors.
- This study investigates the molecular dynamics of FasL/MMP interactions in COVID-19.
Purpose of the Study:
- To explore the molecular dynamics of FasL/MMP7-9 interactions under COVID-19 conditions using in silico methods.
- To provide neuroimmune insights into COVID-19 immunopathology.
- To identify potential therapeutic targets for COVID-19.
Main Methods:
- Clinical cohort analysis of COVID-19 patients, recording blood sodium levels and temperature.
- Molecular dynamics simulations (MDS) using GROMACS for MMP7/FasL and MMP9/FasL systems under healthy and COVID-19 conditions.
- Analysis of binding interactions, salt bridges, hydrogen bonds, and surface area using MDS and MM-GBSA.
- Identification of potential drug targets via machine learning analysis of epitopes.
Main Results:
- MMP9 exhibited a higher number of salt bridges and hydrogen bonds with FasL compared to MMP7 in COVID-19 conditions.
- MMP9 demonstrated greater interacting surface area and residue count with FasL than MMP7.
- Molecular dynamics simulations confirmed stronger binding affinity of MMP9 to FasL.
Conclusions:
- MMP9 displays a stronger interaction with FasL than MMP7, with both maintaining significant binding.
- Identified epitopes within MMP-FasL complexes represent promising therapeutic targets for COVID-19.
- Findings support future efforts in immune drug design and protein repurposing for COVID-19.
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