Effect of Two Point Mutations in Lung Surfactant Protein-D on Enhancing its Inhibition Activity Against Influenza a Virus

Abstract

Lung collectin surfactant proteins are pulmonary host defense proteins that contribute to innate, front-line defense against influenza A virus (IAV) and other inhaled pathogens. Effective pulmonary host defense requires fast recognition by lung surfactant protein D (SP-D) of glycans on the globular head of IAV hemagglutinin (HA), thereby initiating events leading to pathogen neutralization. In site-directed mutagenesis experiments, a double mutant of human SP-D, namely R343V/D325A, was found to enhance IAV neutralization activity. In order to understand the effect of the double mutation on the mechanism of SP-D recognition and inhibition of IAV HA, we performed molecular dynamics simulations on docked SP-D-HA complexes for wild type SP-D (wtSP-D) and double mutant SP-D (dmSP-D). Our simulations revealed that side chain properties of the mutated residues and modes of glycan binding lead to increased binding affinity of dmSP-D to the active site of IVA HA, increasing thereby its antiviral activity.