The physicochemical principles underlying the interactions between proteins and membranes are important for understanding the insertion and folding of membrane proteins, the prediction of membrane protein structure from sequence, and the breaching of the membrane barrier by toxins, antimicrobial peptides, and fusogenic proteins. Just as for the folding of soluble proteins, the details necessary for quantitative predictions remain remarkably elusive even though the basic principles seem clear. We are seeking answers to several broad questions that should help to provide a quantitative structural and thermodynamic framework: (a) Whate is the structure of bilayers with respect to partitioning? (b) Where exavtly do peptides partition into bilayers and what effect do they have on bilayer structure? (c) What are the relative thermodynamic contributins to partitioning of the hydrophobic effect, so-called bilayer effects, and electrostatic effects? (d) How does peptide partitioning affect the formation of secondary structure? This renewal application is concerned with the continued pursuit of answers to these questions by means of structural and thermodynamic studies.
The specific aims of the project are as follows: (1) Finish studies of interfacial partitioning by determining its dependence on lipid composition using host-guest pentapeptides and the antimicrobial peptide indolicidin. (2) Initiate detailed studies of the thermodynamic principles of secondary structure formation at bilayer interfaces using melittin and 16- or 17- residue host-guest peptides of the 'Baldwin' type. (3) Advance the design and use of our transmembrane 'TM' alpha-helical peptide system for determining the thermodynamics of helix insertion into bilayers. (4) Expand structural studies of fluid bilaye-peptide interactions using x-ray and neutron diffraction, NMR spectroscopy, and ATR-FTIR spectroscopy. (5) Clarify the role of tryptophan in membrane protein assembly and stability through studies of the interactions of indole compounds with lipid bilayers.
| Capponi, Sara; Freites, J Alfredo; Tobias, Douglas J et al. (2016) Interleaflet mixing and coupling in liquid-disordered phospholipid bilayers. Biochim Biophys Acta 1858:354-62 |
| Ladokhin, Alexey S; Fernandez-Vidal, Monica; White, Stephen H (2010) CD spectroscopy of peptides and proteins bound to large unilamellar vesicles. J Membr Biol 236:247-53 |
| Jaud, Simon; Fernández-Vidal, Mónica; Nilsson, Ingmarie et al. (2009) Insertion of short transmembrane helices by the Sec61 translocon. Proc Natl Acad Sci U S A 106:11588-93 |
| Snider, Craig; Jayasinghe, Sajith; Hristova, Kalina et al. (2009) MPEx: a tool for exploring membrane proteins. Protein Sci 18:2624-8 |
| Fernandez-Vidal, Monica; Jayasinghe, Sajith; Ladokhin, Alexey S et al. (2007) Folding amphipathic helices into membranes: amphiphilicity trumps hydrophobicity. J Mol Biol 370:459-70 |
| Benz, Ryan W; Nanda, Hirsh; Castro-Roman, Francisco et al. (2006) Diffraction-based density restraints for membrane and membrane-peptide molecular dynamics simulations. Biophys J 91:3617-29 |
| Castro-Roman, Francisco; Benz, Ryan W; White, Stephen H et al. (2006) Investigation of finite system-size effects in molecular dynamics simulations of lipid bilayers. J Phys Chem B 110:24157-64 |
| Benz, Ryan W; Castro-Roman, Francisco; Tobias, Douglas J et al. (2005) Experimental validation of molecular dynamics simulations of lipid bilayers: a new approach. Biophys J 88:805-17 |
| White, Stephen H; von Heijne, Gunnar (2005) Transmembrane helices before, during, and after insertion. Curr Opin Struct Biol 15:378-86 |
| Hristova, Kalina; White, Stephen H (2005) An experiment-based algorithm for predicting the partitioning of unfolded peptides into phosphatidylcholine bilayer interfaces. Biochemistry 44:12614-9 |
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