(376w) Deciphering the Effects of a Triple Mutation on the Structure and Dynamics of Human Interferon Alpha 2-a Via Atomistic Simulations

Interferon Alpha 2-A (IFNα2-A) is a cytokine messenger protein and one of the 16 Type-I Interferons, produced by the cells affected by viruses, bacteria or cancer—to warn nearby healthy cells to uplift their defense against possible infections. IFNα2-A shows anti-viral and anti-proliferative activity and it is used to treat chronic hepatitis B, C, and cancers. All Type-I IFNs signal through the same two receptors: IFNAR1 and IFNAR2; and depending on their binding—the responses vary, making them multifunctional. As the multifunctionality of IFNα2-A causes various side-effects, many mutants such as the triple mutant HEQ (His57Ala, Glu58Ala, and Gln61Ala) were produced intending to minimize the side-effects. HEQ was found to show altered anti-viral and anti-proliferative potencies when compared with wild-type, yet, a proper understanding of the effects of the triple mutation on the structure and dynamics was lacking.

This work presents the results of an atomistic molecular dynamics study carried out to compare various structural and dynamic properties of wild-type IFNα2-A, and its triple mutant, HEQ. The initial structural analysis comparing the two systems showed that the mutation has a minimal effect on the overall structural fold of the protein, whereas the B factor calculations—along with the per residue RMSD and contacts analysis of the IFNAR1 binding site residues—have indicated changes in the local structure and dynamics of the binding site. Further, the dynamic cross-correlation analysis of the two systems has indicated a vivid disparity, showing more negatively correlated residue motions for the mutant and more positive correlations for the wild-type.

These results are expected to provide insights on how the mutation affects the binding of the protein to its receptor subunits when forming the final signaling complex.