Defensins are cationic cysteine-rich small molecules with molecular masses ranging from 3 to 5 kDa. Based on their size and disulfide bonding pattern, defensins can be classified into α, β and θ categories. Human defensins are a critical part of the innate immune system that provides an initial antimicrobial barrier for mucosal surfaces such as the oral cavity, surface of the eyes, airways, lungs, and skin. Human β defensin (hBD) type 3 (hBD-3) is mainly secreted from epithelial cells. It can disrupt both gram-positive and gram-negative cell membranes, and even mammalian cell membrane at high concentrations. However, the structural basis for the membrane-disrupting function of hBD-3 is still unknown.<br/>In this project, explicit solvent and lipid umbrella-sampling simulations were performed using NAMD program to understand the interaction mechanism of hBD-3 with a zwitterionic (but charge-neutral) lipid membrane. In order to consider the hBD-3 structure effect on the translocation free energy barrier, besides hBD-3 wild-type, hBD-3 analog which has three disulfide bonds removed, was also studied. Since hBD-3 can form a dimer at a low concentration, hBD-3 in both monomer and dimer forms through POPC lipid membranes were investigated as well. It was found that hBD-3 in both monomer and dimer forms need to overcome an energy barrier of around 20 kcal/mol to insert into the normal cell lipid membrane center. The hBD-3 dimer in wild-type needs to overcome an energy barrier of 40 kcal/mol to transpass the lipid membrane. Based on the structural analysis on both hBD-3 and lipids around, the result from this project suggests a toroidal model for hBD-3 to transpass through the lipid membrane.

Free-energy studies on human β defensin type 3 through a neutrally charged lipid membrane

2019 Spring National Meeting

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