In Silico Therapeutic Peptide Design Against Pathogenic Domain Swapped Human Cystatin C Dimer

In humans, cystatin C mediated amyloid aggregation is quite detrimental. It is deemed to actuate intra-cerebral haemorrhaging, stroke, paralysis and further, turns out to be fatal under exigent circumstances. Especially, the domain swapped dimerization of cystatin C is the pathogenic trigger that propels its amyloidosis. Targeting the protein at this initial pathogenic stage could be effective in arresting cystatin C amyloid formation and its eventual aggregation. In our current analysis, using a logically assertive coherent computational pipeline, we have proffered an efficacious peptide based therapeutic (due to its benefits over small molecules) against the domain swapped cystatin C amyloid like dimer (CCAD) pre-fibril. Wherein, the tripeptide, 'LVN' has effectually decreased the average beta sheet content (a distinct pathogenic aspect of amyloids) of CCAD from 49 to 43%. Findings from discrete molecular dynamics simulation through intramolecular hydrogen bond analysis, covariance matrix, free energy landscape and solvent accessible surface area have further substantiated that, upon interaction, LVN has steered CCAD from its distinct pathogenic behaviour. Besides, the thermal unfolding simulation indicated that due to LVN's confluence with CCAD, the phase transition of the complex to a flexible state from a rigid phase, occurs with a relatively lower temperature and energy, compared to peptide unbound pathogenic CCAD. Hence, the consistent findings from various computational tools anticipate that LVN tripeptide could be a potent promising candidate in mitigating cystatin C amyloid aggregation in humans.

Automated summary

In humans, cystatin C mediated amyloid aggregation is harmful, but targeting the protein at the initial pathogenic stage with peptide therapy, specifically the 'LVN' tripeptide, could effectively reduce the aggregation and pathogenic behavior of cystatin C amyloidosis.