Effect of external conditions on membrane-protein interactions

Rong Chen (2011). Effect of external conditions on membrane-protein interactions PhD Thesis, School of Chemistry & Molecular Bioscience, The University of Queensland.

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Author Rong Chen
Thesis Title Effect of external conditions on membrane-protein interactions
School, Centre or Institute School of Chemistry & Molecular Bioscience
Institution The University of Queensland
Publication date 2011-04
Thesis type PhD Thesis
Supervisor Prof Alan Mark
A/Prof Serdar Kuyucak
Prof Joe Lynch
Total pages 139
Total colour pages 16
Total black and white pages 123
Subjects 03 Chemical Sciences
Abstract/Summary Proteins that either embed permanently in membranes or must attach to membranes to be functional are one of the most important classes of biomolecules. For example, approximately 50% of available drugs target membrane proteins. Despite their important role in biology and medicine, the mechanism by which such membrane proteins function is still not well understood. This is partially due to the fact that the ability of currently available experimental techniques to study interactions of proteins is limited. In contrast, computational approaches, such as the molecular dynamics (MD) simulation technique, allow the molecular interactions in such systems to be examined in atomic detail. In this thesis, MD simulations have been applied into a number of membrane protein systems, in an attempt to further our understanding of membrane protein interactions. This thesis focuses on understanding five questions: what is 1) the effect of high pressure on the structure and phase transition of fully hydrated DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and POPC (2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine) bilayers? 2) the effect of NaCl on the structure of fully hydrated POPC bilayers? 3) the effect of membrane curvature on the conformation of antimicrobial peptides? 4) the mechanism by which the antimicrobial peptide kalata B1 (KB1) forms transmembrane pores? 5) the effect of high pressure on the structure and gating of the bacterial mechanosensitive channel of small conductance (MscS)? The simulations suggest that lipid bilayers in a rippled gel phase consist of a major ordered regions and a minor disordered region, in line with earlier proposals, and also indicate that it is possible to reproduce the phase behaviour of lipid bilayers as a function of pressure using the latest GROMOS 54a7 force field for lipids. However, when this force field was used to simulate a POPC bilayer containing NaCl, the bilayer was too compact and thicker than compared to experiment, suggesting that the force field parameters for describing lipid-ion interactions may be further optimized. The conformation of four selected antimicrobial peptides isolated from Australian frogs (aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1) in a range of solvent and membrane environments, including water, 50%v TFE (2,2,2-trifluoroethanol) in water, DPC (dodecylphosphocholine) micelles, a POPC bilayer containing a toroidal pore, and a planar DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) bilayer, were investigated. The secondary structure of the peptides on binding to membranes was found to be correlated with the curvature of membrane and the length of peptide. Specifically, the longer peptides, citropin, maculatin and caerin, were more helical on binding to curved membranes than flat membranes, while the shortest peptide aurein maintained similar helical content on binding to the different membranes. The simulations also suggest that TFE and micelles are not substitutes for membrane environments. The aggregation of KB1 in POPC bilayers was examined. The simulations predicted the orientation of KB1 on binding into membranes and the association of KB1 into tetramers through nonpolar residues, consistent with experiment. In addition, the time evolution of a barrel-stave pore preformed by a ring of eight KB1 dimers was investigated. It was found that the pore diameter shrank substantially from 4.5 to 2.0 nm after 90 ns of simulation at 400 K, and the lipids near the pore bend their head groups continuously toward the pore forming a toroidal nature. Moreover, the effect of KB1 binding on the stability of a toroidal pore in a POPC bilayer was also examined. It was found that the pore became significantly more stable on peptide binding. Overall, the simulations suggest a toroidal pore mechanism for KB1. Finally, the simulations suggest that a pressure of 1000 atm can induce significant structural changes in both the MscS channel and the lipid bilayer in which the channel embeds. In particular, the lipid bilayer was thinner, and the pore of MscS was less stable and more resistant to lateral membrane tension at 1000 atm than at 1 atm. The simulations could largely explain the gating of MscS as a function of pressure observed experimentally.
Keyword Lipid bilayer
membrane protein
mechanosensitive channel
Antimicrobial peptide
Hydrostatic pressure
molcular dynamics
Additional Notes 19, 22, 23, 44, 65, 77, 78, 79, 84, 91, 93, 95, 96, 101, 108, 109

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Created: Tue, 25 Oct 2011, 14:09:31 EST by Mr Rong Chen on behalf of Library - Information Access Service