Molecular dynamics simulations of perforin mutations associated with familial hemophagocytic lymphohistiocytosis type 2 among Indian patients.
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Cytotoxic lymphocyte pore-forming protein termed perforin-1 (PFP) produced by NK and CD8+ T cells plays a critical role in viral and tumor-related immunity. Deleterious mutations in the gene encoding PFP lead to its dysfunction and impaired cytotoxic activity, causing hemophagocytic lymphohistiocytosis. Familial hemophagocytic lymphohistiocytosis type 2 is a rare, life-threatening, hyperinflammatory disorder that predominantly affects infants and children. Current treatment strategies are often harsh with poor prognosis, making it crucial to understand the disease etiology toward developing future therapeutics. The aim of this study was to investigate the structural changes occurring in the mature soluble form of PFP to better understand disease pathogenesis. Molecular dynamics simulations were employed to study the conformational changes and stability of Ca2+ in the calcium-binding regions (CBR) of the C2 domain. Twelve highly conserved pathogenic mutations reported among Indian patients were analyzed of which the E261K mutation exhibited the most significant conformational changes, including the loss of a TMH2 motif. Mutations like G305S and G220R caused allosteric destabilization of the CBR indicating that alterations at one site can affect other functional domains. All mutant structures displayed changes in rigidity, with site III of the CBR particularly affected, suggesting diminished activity in the soluble state and impaired function. This study has identified a pattern linking disease severity to specific structural disruptions. Our comprehensive in silico study highlights that these mutations lead to structural and functional alterations ultimately contributing to the disease phenotype.