Nano-Mechanical Tensile Behavior of the SPTA1 Gene in the Presence of Hereditary Hemolytic Anemia-Related Point Mutations

Hunt M.

BIOMEDICAL TECHNOLOGY: MODELING, EXPERIMENTS AND SIMULATION, vol.84, pp.35-47, 2018 (SCI-Expanded) identifier identifier


A skeletal network of spectrin molecules provides shear stiffness to the red blood cell (RBC) membrane maintaining its shape (by providing elasticity) and thus its stability. There are two a and two beta subunits of human spectrin; the alpha 1 and beta 1 spectrin subunits are encoded SPTA1 and SPTB, respectively. Hereditary elliptocytosis (HE), one of the hereditary blood disorders, results in elliptical/oval, elongated RBCs due to the abnormalities that occur mainly at the atomistic level because of the mutations in SPTA1 and SPTB. In HE, the RBC membrane partly loses its elasticity and this results in a reduced overall durability of RBCs. In its severe forms, hereditary blood disorders can lead to hemolytic anemias when the abnormal RBCs start to depreciate. This study aims to observe mechanically how the abnormalities due to the mutations in SPTA1 gene affect single spectrin molecules. The stiffness of the mutated and normal/wild-type molecules are calculated using Steered Molecular Dynamics (SMD) by subjecting the spectrin a chain to displacements up to tens of nanometers and drawing force-extension maps from these computational experiments. The most common HE mutations being SPTA1 gene missense mutations in the dimer-tetramer self-association site makes it interesting to introduce mutations at the binding site and compare the change in the mechanical response of the mutated molecules to that of the wild-type. Overall, the results presented here show that the nano-mechanical tensile behaviour at the chain-level does not change under the presence of the point mutations. This suggests that the local structural disturbances the mutations cause, will affect the spectrin scaffold on the network-level rather than on the on the single chain level implying more complicated molecular interactional disorders. The work presented here is a part of a larger effort to improve understanding the functional implications of the mechanical and structural properties of proteins starting at the atomistic level.