Molecular simulation unravels the amyloidogenic misfolding of nascent ApoA1 protein, driven by deleterious point mutations occurring in between 170-178 hotspot region.

Protein ApoA1 is extensively studied for its role in lipid metabolism. Its seedy dark side of amyloid formulation remains relatively understudied yet. Due to genetic mutations, the protein pathologically misshapes into its amyloid form that gets accumulated in various organs, including the heart. To contrive effective therapeutics against this debilitating congenital disorder, it is imperative to comprehend the structural ramifications induced by mutations in APoA1's dynamic conformation. Till now, several point mutations have been implicated in ApoA1's amyloidosis, although only a handful has been examined considerably. Especially, the single nucleotide polymorphisms (SNPs) that occur in-between 170-178 mutation hotspot site of APoA1 needs to be investigated, since most of them are culpable of amyloid deposition in the heart. To that effect, in the present study, we have computationally quantified and studied the ApoA1's biomolecular modifications fostered by SNPs in the 170-178 mutation hotspot. Findings from discrete molecular dynamics simulation studies indicate that the SNPs have noticeably steered the ApoA1's behaviour from its native structural dynamics. Analysis of protein's secondary structural changes exhibits a considerable change upon mutations. Further, subjecting the protein structures to simulated thermal denaturation shows increased resistance to denaturation among mutants when compared to native. Further, normal mode analysis of protein's dynamic motion also shows discrepancy in its dynamic structural change upon SNP. These structural digressions induced by SNPs can very well be the biomolecular incendiary that drives ApoA1 into its amyloidogenesis. And, understanding these structural modifications initiates a better understanding of SNP's amyloidogenic pathology on APoA1.Communicated by Ramaswamy H. Sarma.