Molecular dynamics simulations as a tool for the study and structure-guided engineering of type III interferons

Type III interferons (IFNλ1-4) are proteins which combat viral infections and cancer and have naturally targeted activity due to tissue-specific receptor expression. However, their low activity relative to type I IFNs has limited their clinical use. Previous work used an engineered, high-affinity IFNλ3 (H11) to increase its antiviral and antiproliferative properties as well as solve the crystal structure of the ligand-receptor complex; however, the total differences in behavior between H11 and wild type IFNλs are unknown, and the activity of H11 is still lower than type I IFN. To better study and engineer IFNλs, we use molecular dynamics (MD) simulations to model the H11 and IFNλ3 complexes. Using trajectory and free energy data, we quantify differences in residue contact, strain, and fluctuation experienced by the protein complexes, reveal novel structural differences, and estimate the individual contributions of the residues to binding. These simulations reveal regions of the proteins that can be engineered to improve both complex stability and IFNλ activity. In combination with experimental techniques, future work using MD as a tool to study ligand-receptor complexes can expedite and improve approaches to solving crystal structures and develop more effective therapeutics.