Browsing by Subject "Antimicrobial peptide"
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Item A comprehensive study of cholesterol in biomembranes using computer simulations(2011-05) Dai, Jian; Huang, Juyang; Park, Soyeun; Sanati, Mahdi; Khare, RajeshSeveral methods were applied to study the effects of cholesterol on multi-component lipid bilayers. The goal is to investigate the validity of the "Umbrella Effect" via simulations and experiments. The Umbrella Model is a hypothesis proposed based on previous structural and thermodynamical studies of lipid membranes containing cholesterol. DPPC is the most widely studied phospholipid in the simulation community. It has a large polar headgroup (which consists of a positively charged choline group and a negatively charged phosphate group), a glycerol group and two long saturated hydrocarbon chains. On the other hand, cholesterol has a relatively large carbon-ring body, compared to its small hydrophilic hydroxyl group. When a binary mixture of DPPC/cholesterol is placed in an aqueous environment, it has been suggested that cholesterol is always trying to find a “shield” to protect it from extensive contact with water, and this shield is most likely to be provided by the headgroups of phospholipids. This hypothesis is termed the “Umbrella Model”. Monte Carlo (MC) simulations will be used to study the phase transitions of multi-component lipid mixtures and molecular dynamics (MD) simulations will be used to test the Umbrella Model in direct and indirect ways, and to interpret the experimental data. Melittin is the most studied antimicrobial peptide, it can cause cell death by damaging cell membranes. Melittin interacts differently with various membrane components, such as cholesterol and negatively-charged phospholipid, both of which have been shown to reduce melittin's lytic effect against the membrane. Several model systems were constructed and simulated, different effects were observed and the possible mechanisms were discussed.Item Membrane remodeling in epsilon proteobacteria and its impact on pathogenesis(2012-05) Cullen, Thomas Wilson; Trent, Michael Stephen; Whiteley, Marvin; Harshey, Rasika M.; Stevens, Scott W.; O'Halloran, Terry J.Bacterial pathogens assemble complex surface structures in an attempt to circumvent host immune detection. A great example is the glycolipid known as lipopolysaccharide or lipooligosaccharide (LPS), the major surface molecule in nearly all gram-negative organisms. LPS is anchored to the bacterial cell surface by a anionic hydrophobic lipid known as lipid A, the major agonist of the mammalian TLR4-MD2 receptor and likely target for cationic antimicrobial peptides (CAMPs) secreted by host cells (i.e. defensins). In this work we investigate LPS modification machinery in related ε-proteobacteria, Helicobacter pylori and Campylobacter jejuni, two important human pathogens, and demonstrate that enzymes involved in LPS modification not only play a role in evasion of host defenses but also an unexpected role in bacterial locomotion. More specifically, we identify the enzyme responsible for 4'-dephosphorylation of H. pylori lipid A, LpxF. Demonstrating that lipid A depohsphorylation at the 1 and 4'-positions by LpxE and LpxF, respectively, are the primary mechanisms used by H. pylori for CAMP resistance, contribute to attenuated TRL4-MD2 activation and are required for colonization of a the gastric mucosa in murine host. Similarly in C. jejuni, we identify an enzyme, EptC, responsible for modification of lipid A at both the 1 and 4'-positions with phosphoethanolamine (pEtN), also required for CAMP resistance in this organism. Suprisingly, EptC was found to serve a dual role in modifying not only lipid A with pEtN but also the flagellar rod protein FlgG at residue Thr75, required for motility and efficient flagella production. This work links membrane biogenesis with flagella assembly, both shown to be required for colonization of a host and adds to a growing list of post-translational modifications found in prokaryotes. Understanding how pathogens evade immune detection, interphase with the surrounding environment and assemble major surface features is key in the development of novel treatments and vaccines.