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Insertion of Dengue E into lipid bilayers studied by neutron reflectivity and molecular dynamics simulations.

ABSTRACT: The envelope (E) protein of Dengue virus rearranges to a trimeric hairpin to mediate fusion of the viral and target membranes, which is essential for infectivity. Insertion of E into the target membrane serves to anchor E and possibly also to disrupt local order within the membrane. Both aspects are likely to be affected by the depth of insertion, orientation of the trimer with respect to the membrane normal, and the interactions that form between trimer and membrane. In the present work, we resolved the depth of insertion, the tilt angle, and the fundamental interactions for the soluble portion of Dengue E trimers (sE) associated with planar lipid bilayer membranes of various combinations of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-glycerol (POPG), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), and cholesterol (CHOL) by neutron reflectivity (NR) and by molecular dynamics (MD) simulations. The results show that the tip of E containing the fusion loop (FL) is located at the interface of the headgroups and acyl chains of the outer leaflet of the lipid bilayers, in good agreement with prior predictions. The results also indicate that E tilts with respect to the membrane normal upon insertion, promoted by either the anionic lipid POPG or CHOL. The simulations show that tilting of the protein correlates with hydrogen bond formation between lysines and arginines located on the sides of the trimer close to the tip (K246, K247, and R73) and nearby lipid headgroups. These hydrogen bonds provide a major contribution to the membrane anchoring and may help to destabilize the target membrane.

SUBMITTER: Vanegas JM

PROVIDER: S-EPMC6532988 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Insertion of Dengue E into lipid bilayers studied by neutron reflectivity and molecular dynamics simulations.

Vanegas Juan M JM Heinrich Frank F Rogers David M DM Carson Bryan D BD La Bauve Sadie S Vernon Briana C BC Akgun Bulent B Satija Sushil S Zheng Aihua A Kielian Margaret M Rempe Susan B SB Kent Michael S MS

Biochimica et biophysica acta. Biomembranes 20180213 5

The envelope (E) protein of Dengue virus rearranges to a trimeric hairpin to mediate fusion of the viral and target membranes, which is essential for infectivity. Insertion of E into the target membrane serves to anchor E and possibly also to disrupt local order within the membrane. Both aspects are likely to be affected by the depth of insertion, orientation of the trimer with respect to the membrane normal, and the interactions that form between trimer and membrane. In the present work, we res ...[more]

PMID: 29447917

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Project description:Human β defensin type 3 (hBD-3) is a small cationic cysteine-rich peptide. It has a broad spectrum of antimicrobial activities. However, at high concentrations, it also shows hemolytic activity by interrupting red blood cells. To understand the selectivity of hBD-3 disrupting cell membranes, investigating the capability of hBD-3 translocating through different membranes is important. Since hBD-3 in the analogue form in which all three pairs of disulfide bonds are broken has similar antibacterial activities to the wild-type, this project investigates the structure and dynamics of an hBD-3 analogue in monomer, dimer, and tetramer forms through both zwitterionic and negatively charged lipid bilayers using molecular dynamics (MD) simulations. One tetramer structure of hBD-3 was predicted by running all-atom MD simulations on hBD-3 in water at a high concentration, which was found to be stable in water during 400 ns all-atom simulations based on root-mean-squared deviation, root-mean-squared fluctuation, buried surface area, and binding interaction energy calculations. After that, hBD-3 in different forms was placed inside different membranes, and then steered MD simulation was conducted to pull the hBD-3 out of the membrane along the z-direction to generate different configurational windows to set up umbrella-sampling (US) simulations. Because extensive sampling is important to obtain accurate free energy barriers, coarse-grained US MD simulations were performed in each window. Based on the long-term simulation result, membrane thinning was found near hBD-3 in different lipid bilayers and in different hBD-3 oligomer systems. By calculating the root-mean-squared deviation of the z-coordinate of hBD-3 molecules, rotation of the oligomer inside the bilayer and stretching of the oligomer structure along the z-direction were observed. Although reorientation of lipid heads toward the hBD-3 tetramer was observed based on the density profile calculation, the order parameter calculation shows that hBD-3 disrupts 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS) lipids more significantly and makes it less ordered than on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. Calculating the free energy of hBD-3 through different lipid bilayers, it was found that generally hBD-3 encounters a lower energy barrier through negatively charged lipid membranes than the zwitterionic membrane. hBD-3 in different forms needs to overcome a lower energy barrier crossing the combined POPC+POPS bilayer through the POPS leaflet than through the POPC leaflet. Besides that, the potential of mean force result suggests that hBD-3 forms an oligomer translocating negatively charged lipid membranes at a low concentration. This study supplied new insight into the antibacterial mechanism of hBD-3 through different membranes.

Dataset Information

Insertion of Dengue E into lipid bilayers studied by neutron reflectivity and molecular dynamics simulations.

Publications

Insertion of Dengue E into lipid bilayers studied by neutron reflectivity and molecular dynamics simulations.

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