Molecular dynamics simulations corroborate recombinant expression studies carried out on three αIIb β-propeller mutations reported in Indian Glanzmann thrombasthenia patients.

Mutations in the αIIb β-propeller domain have long been known to disrupt heterodimerization and intracellular trafficking of αIIbβ3 complexes leading to diminished surface expression and/or function, resulting in Glanzmann thrombasthenia. Our previous study on three β-propeller mutations, namely G128S, S287L, and G357S, showed variable defects in protein transport correlated with the patient's clinical phenotypes. Pulse-chase experiments revealed differences in αIIbβ3 complex maturation among the three mutations. Hence, the current study aims to correlate conformational changes caused by each one of them. Evolutionary conservation analysis, stability analysis, and molecular dynamics simulations of the three mutant structures were carried out. Stability analysis revealed that, while G128S and G357S mutations destabilized the β-propeller structure, S287L retained the stability. Wild-type and mutant β-propeller structures, when subjected to molecular dynamics simulations, confirmed that G128S and G357S were both destabilizing in nature when compared with the wild-type and S287L based on several parameters studied, like RMSD, RMSF, Rg, FEL, PCA, secondary structure, and hydrogen bonds. In our previous study, we demonstrated that mutant S287L αIIbβ3 complexes were more stable than the wild-type αIIbβ3 complexes, as evidenced in pulse-chase experiments. These findings corroborate variable intracellular fates of mutant αIIbβ3 complexes as a result of these β-propeller mutations.