Immunoinformatics analysis of Fas/MMP-FasL interactions to evaluate molecular basis of cytokine storm activation in COVID-۱۹ patients

Background: The coronavirus disease-۲۰۱۹ (COVID-۱۹) pandemic is still ongoing. Cytokinestorm has been used to describe the harmful cytokines that induce cellular damage. Such mechanismshave been linked to multi-system injury in COVID-۱۹. In ۲۰۲۱, we proposed a pathwayfor initiation of cytokine storm by MMPs with Fas/FasL interactions (DOI: ۱۰.۱۵۱۵/revneuro-۲۰۲۱-۰۰۴۷). Here, we conduct in silico analysis of these interactions in different blood-likecontexts, such as hyponatremia in context of COVID-۱۹ patients. We also attempt to link suchchanges in blood profile of COVID-۱۹ patients to Fas or FasL with MMP interactions, that maylead to subsequent cellular damage.Methods: We comparatively docked Fas/MMP-FasL complexes by HDock, Autodock/AUTOGRID۴,and Autodock Vina tools. Patchdock was used to select the most stable complex. Then,we performed molecular dynamics analysis via GROningen MAchine for Chemical Simulations(GROMACS) for ۱۰ ns. Na+ and Cl- ions were used. Also, different blood osmolarities weresimulated (e.g., hyponatremia: ۱۳۰ Na level vs normal Na level: ۱۴۰ Na level). Advanced bindingenergy analyses were utilized. All-atom OPLSAA forcefield was used. Pressure coupling usingthe Parinello-Rahman method based on constant NPT ensemble. PBC XYZ boundaries were usedin a triclinic box for the purpose of simulation.Results: Analyses showed MMP-Fas(L) interactions varied among different Na+/Cl- concentrations.Hyponatremia was associated with stronger interactions. Negative molecular mechanicsPoisson-Boltzman Surface Analysis (MM-PBSA) (van der Waal energy, Electrostattic energy,Polar solvation energy, SASA energy, SAV energy, WCA energy) energies were detected. Also,contact residues in the stabilized complexes were increased by the COVID-۱۹-like hyponatremiablood environment. For MMP-FasL simulation, the complex was minimized in with target Fmax< ۱۰۰۰ in ۱۹۱۰ steps, Potential energy reached -۱.۲۳۱۱۶۱۱e+۰۶, which is favorably negative.We found negative binding energies. RMSD of MMP-FasL complex reached stability after ۵ns.RMSF and gyration analysis and visualization of the complex did not show denaturation or severeexpansion/fluctuation of the protein complex. For a MMP-FasL simulation, contact residueswere increased. MMP-FasL interaction in COVID-۱۹ conditions showed VDW, ELE, GB, SA,TOTAL energies were -۱۷۰.۵۳, -۱۲.۸۲, ۱۴۶.۶۷, -۱۸.۹۱, -۵۵.۶۰ kcal/mol, respectively.Conclusions: Our analyses highlighted that clinical profile (e.g., electrolytes) could influence interactionsamong key players in the cytokine storm in COVID-۱۹. Currently, we are conductingclinical research by analyzing the regulation of these players in COVID-۱۹ patients. Some methodssuch as WGCNA can be used in future studies to compute the correlation between cytokinesand clinical traits.

کلیدواژه ها:

Immunology ، COVID-۱۹ ، FasL ، Cytokine storm ، Molecular dynamics Simulation