Our body uses several defense mechanisms against seasonal flu, the common affliction caused by influenza viruses. By taking a yearly flu shot, our body’s defense based on antibodies is trained and envoked. A defense system not based on antibodies acts at the very front line of influenza virus attack, namely the lungs. For this protection the body uses so-called lung surfactant proteins that coat the inner lining of the lungs to keep a wet film on the lung surface needed for oxygen-carbon dioxide exchange. The lung surfactant proteins also serve as police against influenza viruses. For this purpose the lung surfactant protein D (SP-D) recognizes a protein component of the virus surface, namely hemagglutinin, and handcuffs the sugar molecules bound to hemagglutinin. Now, we have boosted the protective ability of human SP-D by introducing mutations. Molecular dynamics simulations using NAMD suggest that the mutated human SP-D employs a different and stronger blocking mechanism on the active site of influenza A virus than native SP-D does. Combined with experimental results, the simulations suggest a mechanism through which SP-D acts, namely, by handcuffing viruses together and, thereby, preventing viral entry into cells. The findings from this research might lead to a new protection against seasonal flu, namely a nasal spray containing mutated lung surfactant proteins that strengthen a person’s armada of defense proteins on the lung surface.
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.
Lung collectin surfactant protein A (SP-A) is a pulmonary host defense protein that contributes to the innate defense against inhaled microorganisms. SP-A is known to aggregate dipalmitoylphosphatidylcholine (DPPC) lipid to form tubular myelin, a highly structured form of surfactant lipids and proteins. In this study, we employed x-ray crystallography and molecular dynamics simulations to investigate the binding mechanism of SP-A to DPPC. Our simulations revealed that the SP-A binds to the phosphate and choline groups of DPPC via hydrogen bonding and cation-pi interactions, respectively. In particular, a box-like structure formed by three tyrosine residues of SP-A was observed to consistently bind to the choline group of DPPC, suggesting the box structure to be part of the primary lipid binding site. Additionally, DPPC was found to diffuse slower once bound to SP-A. The aggregation of DPPC by SP-A suggests a possible formation of SP-A array that optimizes the surface properties of surfactant and the interception of inhaled microbes at the air-lung interface.