This is a computational investigation of how point mutations in surfactant protein D (SP-D) enhance its binding affinity with viral glycans. SP-D is an essential component of the human pulmonary surfactant system, which is crucial in the innate immune response against glycan-containing pathogens, including Influenza A viruses (IAV) and SARS-CoV-2. Previous studies have shown that wild-type (WT) SP-D can bind IAV but exhibits poor antiviral activities. However, a double mutant (DM) SP-D consisting of two point mutations (Asp325Ala and Arg343Val) inhibits IAV more potently. We use microsecond-scale, full-atomistic molecular dynamics (MD) simulations, combing with free energy perturbation (FEP) and quantum mechanics to understand how Asp325Ala and Arg343Val mutations enhance SP-D's ability to bind viral glycans. We utilized 12 models considering different point mutations and different viral glycan binding poses and ran each model for over 3,000 ns MD simulation. Our critical analyses of binding affinities of wild-type SP-D and a double mutant SP-D explain previous experimental results of the enhanced antiviral activity of mutant SP-D. The results of this study are vital for further designing potential SP-D to inhibit pathogens with higher binding specificity. The findings of this study have been published (Li and Minkara 2022).

Elucidating the enhanced binding affinity of a double mutant SP-D with trimannose on the influenza A virus using molecular dynamics

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