The importance of the large group of collectin family of proteins, Surfactant Protein A (SP-D), Surfactant Protein D (SP-D) and Mannose Binding Lectin (MBL), in the fight against lung related infections has become an active area of study
1,2. These carbohydrate-binding proteins (C-type lectins) bind to surface carbohydrate structures of pathogens, flagging them for phagocytosis and enhancing their clearance from the lungs. Despite the critical roles played in host innate immunity and response to several lung infections, the underlying molecular mechanisms of their binding still remains elusive or not well defined. Previous studies have characterised the glycan-binding specificities of SP-D as well as exploring how point mutations lead to enhancement of glycan binding
3–5. The findings revealed a unique binding interaction profile of SP-D providing a mechanistic explanation of the preferential binding mode of SP-D and thus laying the ground work for exploration of binding patterns of collectins against various other pathogens. The aim of this study therefore is to investigate the interaction of SP-A, SP-D and MBL with viral glycans and perform a comparative analysis of these interactions using a suite of advanced computational modeling techniques. The first phase of this study will investigate the interactions between SP-A, SP-D and MBL with viral glycan libraries using Induced Fit Docking (IFD), Binding Pose Metadynamics (BPMD) and Molecular Dynamics (MD) simulations studies to explore and identify their stability, flexibility, thermodynamic and energetic favourability. Then, a comparative analysis will be performed to investigate the shared or divergent binding motifs among these proteins. More precisely, we will perform a systematic evaluation of conformational dynamics, binding energy landscapes, and interaction hotspots across the repertoire of collectin-viral glycan complexes. Insights gained from this comparative analysis could help us engineer possible therapeutics.
References
(1) Clark, H. W.; Reid, K. B. M.; Sim, R. B. Collectins and Innate Immunity in the Lung. Microbes Infect. 2000, 2 (3), 273–278. https://doi.org/10.1016/S1286-4579(00)00301-4.
(2) Wu, H.; Kuzmenko, A.; Wan, S.; Schaffer, L.; Weiss, A.; Fisher, J. H.; Kim, K. S.; McCormack, F. X. Surfactant Proteins A and D Inhibit the Growth of Gram-Negative Bacteria by Increasing Membrane Permeability. J. Clin. Invest. 2003, 111 (10), 1589–1602. https://doi.org/10.1172/JCI16889.
(3) Hsieh, I.-N.; De Luna, X.; White, M. R.; Hartshorn, K. L. The Role and Molecular Mechanism of Action of Surfactant Protein D in Innate Host Defense Against Influenza A Virus. Front. Immunol. 2018, 9, 1368. https://doi.org/10.3389/fimmu.2018.01368.
(4) Goh, B. C.; Rynkiewicz, M. J.; Cafarella, T. R.; White, M. R.; Hartshorn, K. L.; Allen, K.; Crouch, E. C.; Calin, O.; Seeberger, P. H.; Schulten, K.; Seaton, B. A. Molecular Mechanisms of Inhibition of Influenza by Surfactant Protein D Revealed by Large-Scale Molecular Dynamics Simulation. Biochemistry 2013, 52 (47), 8527–8538. https://doi.org/10.1021/bi4010683.
(5) Li, D.; Minkara, M. S. Elucidating the Enhanced Binding Affinity of a Double Mutant SP-D with Trimannose on the Influenza A Virus Using Molecular Dynamics. Comput. Struct. Biotechnol. J. 2022, 20, 4984–5000. https://doi.org/10.1016/j.csbj.2022.08.045.
