The impact of missense mutation in PIGA associated to paroxysmal nocturnal hemoglobinuria and multiple congenital anomalies-hypotonia-seizures syndrome 2: A computational study

Heliyon

Gianluca Gatto¹  Enrico Pieroni²  Amit Kumar³  Ashish Kumar Agrahari⁴ 

[1] Corresponding author.;Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;;CRS4 – Modeling &Department of Integrative Biology, School of Biosciences and Technology, VIT, Vellore, Tamil Nadu 632014, India;

关键词: Biophysics;    Condensed matter physics;    Computational chemistry;    Theoretical chemistry;    Bioinformatics;    Missense mutations;   

DOI  :  

来源: DOAJ

【 摘 要 】

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. The disease is caused by the deficiency of two glycosylphosphatidylinositols (GPI)-anchored proteins (CD55 and CD59) in the hemopoietic stem cells. The deficiency of GPI-anchored proteins has been associated with the somatic mutations in phosphatidylinositol glycan class A (PIGA). However, the mutations that do not cause PNH is associated with the multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2). To best of our knowledge, no computational study has been performed to explore at an atomistic level the impact of PIGA missense mutations on the structure and dynamics of the protein. Therefore, we focused our study to provide molecular insights into the changes in protein structural dynamics upon mutation. In the initial step, screening for the most pathogenic mutations from the pool of publicly available mutations was performed. Further, to get a better understanding, pathogenic mutations were mapped to the modeled structure and the resulting protein was subjected to 100 ns molecular dynamics simulation. The residues close to C- and N-terminal regions of the protein were found to exhibit greater flexibility upon mutation. Our study suggests that four mutations are highly effective in altering the structural conformation and stability of the PIGA protein. Among them, mutant G48D was found to alter protein's structural dynamics to the greatest extent, both on a local and a global scale.

【 授权许可】

Unknown