In silico analysis of Glanzmann variants of Calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect

Abstract

Integrin α_IIbβ₃ mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), α_IIbβ₃ expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of α_IIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures. The most flexible region of Calf-1 (with highest B-factor) is rather a rigid region encompassed into two deformable zones. Each mutated structure barely showed any modifications at the mutation sites while distant conformational changes were observed. These unexpected results question the relationship between molecular dynamics and allostery; and the role of these long-range effects in the impaired α_IIbβ₃ expression. This method is aimed at studying all α_IIbβ₃ sub-domains and impact of missense mutations at local and global structural level.