Metadynamics study of mutant human interferon-gamma forms

Abstract

Human interferon-gamma (hIFN-γ) is an important antiviral and immunomodulating signaling molecule. The upregulation of its production, however, is related to the etiology of certain autoimmune diseases. In the search for a mechanism for suppressing the hIFN-γ biological activity, we investigated the possibility to obtain mutant derivatives of the protein, capable to bind to hIFN-γ cellular receptors, but lacking the ability to trigger the biological response inside the cell. In order to preserve the affinity to the receptor, the introduced mutations should not induce conformational changes in the secondary structure of the mutants. Molecular dynamics simulations were performed to study the secondary structure of 100 randomly chosen hIFN-γ derivatives with substitutions in amino acids 86–88. The stability of the local structure of all hIFN-γ forms was investigated by means of metadynamics. It was found that some of the mutated forms preserve the local secondary structure and show similar or higher stability of the mutated helix, compared to the native form. The 12 most promising mutants were suggested for experimental investigation.