Single amino acid substitutions in the
globin chain are the most common forms of genetic variations that produce
hemoglobinopathies--the most widespread inherited disorders worldwide. Several
hemoglobinopathies result from homozygosity or compound heterozygosity to
beta-globin (HBB) gene mutations, such as that producing sickle cell
hemoglobin (HbS), HbC, HbD and HbE. Several of these mutations are deleterious and result in moderate to severe
hemolytic anemia, with associated complications, requiring lifelong care and management. Even though many
hemoglobinopathies result from single
amino acid changes producing similar structural abnormalities, there are functional differences in the generated variants. Using in silico methods, we examined the genetic variations that can alter the expression and function of the HBB gene. Using a sequence homology-based Sorting Intolerant from Tolerant (SIFT) server we have searched for the SNPs, which showed that 200 (80%) non-synonymous polymorphism were found to be deleterious. The structure-based method via PolyPhen server indicated that 135 (40%) non-synonymous polymorphism may modify
protein function and structure. The Pupa Suite software showed that the SNPs will have a phenotypic consequence on the structure and function of the altered
protein. Structure analysis was performed on the key mutations that occur in the native
protein coded by the HBB gene that causes
hemoglobinopathies such as: HbC (E→K), HbD (E→Q), HbE (E→K) and HbS (E→V). Atomic Non-Local Environment Assessment (ANOLEA), Yet Another Scientific Artificial Reality Application (YASARA), CHARMM-GUI webserver for macromolecular dynamics and mechanics, and Normal Mode Analysis, Deformation and Refinement (NOMAD-Ref) of Gromacs server were used to perform molecular dynamics simulations and energy minimization calculations on β-Chain residue of the HBB gene before and after mutation. Furthermore, in the native and altered
protein models,
amino acid residues were determined and secondary structures were observed for
solvent accessibility to confirm the protein stability. The functional study in this investigation may be a good model for additional future studies.