Defensin-based therapeutic peptide design in attenuating V30M TTR-induced Familial Amyloid Polyneuropathy.

In the present study, we aimed to formulate an effective therapeutic candidate against V30M mutant transthyretin (TTR) protein to hinder its pathogenic misfolding. Nicotiana alata Defensin 1 (NaD1) Antimicrobial Peptide (AMP) was availed due to its tendency to aggregate, which may compete for aggregation-prone regions of pathogenic TTR protein. Based on NaD1's potential to bind to V30M TTR, we proposed NaD1-derived tetra peptides: CKTE and SKIL to be initial therapeutic candidates. Based on their association with mutant TTR protein, CKTE tetra peptide showed considerable interaction and curative potential as compared to SKIL tetra peptide. Further analyses from discrete molecular dynamics simulation corroborate CKTE tetra peptide's effectiveness as a 'beta-sheet breaker' against V30M TTR. Various post-simulation trajectory analyses suggested that CKTE tetra peptide alters the structural dynamics of pathogenic V30M TTR protein, thereby potentially attenuating its beta-sheets and impeding its aggregation. Normal mode analysis simulation corroborated that V30M TTR conformation is altered upon its interaction with CKTE peptide. Moreover, simulated thermal denaturation findings suggested that CKTE-V30M TTR complex is more susceptible to simulated denaturation, relative to pathogenic V30M TTR; further substantiating CKTE peptide's potential to alter V30M TTR's pathogenic conformation. Moreover, the residual frustration analysis augmented CKTE tetra peptide's proclivity in reorienting the conformation of V30M TTR. Therefore, we predicted that the tetra peptide, CKTE could be a promising therapeutic candidate in mitigating the amyloidogenic detrimental effects of V30M TTR-mediated familial amyloid polyneuropathy (FAP). Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03646-4.

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.