Protein interactions, phospholipid

The interactions of several peptides with phospholipids have been studied by computer simulation. Emphasis has been given to several aspects of protein-phospholipid interactions, including the way of association and orientational preference of peptides in contact with a bilayer, the effect of phospholipids on the preference and stability of helical conformations, and the effect of the inserted peptide on the structure and dynamics of the phospholipids. These investigations have been extended to bundles of helices and even whole pore-forming proteins. In particular, the simulation of ion channels and of peptides with antimicrobial action has attracted a great deal of attention in theoretical studies. 

Lange, C., Nett, J.H., Trumpower, B.L. and Hunte, C., Specific roles of protein-phospholipid interactions in the yeast cytochrome bcl complex structure, Embo J 20 (2001) 6591-6600. 

Note added in proof. The same conclusion has been arrived at by Sixl, F. GaUa, H-J. Biochim. Biophys. Acta 1982, 693, 466-478, who used the approach described in for studying the interaction between an acidic phospholipid and a low molecular weight, postively charged protein polymixin. Therefore PVPC6 is a reasonable model for the study of protein-phospholipid interaction. 

Paris, S., Beraud-Dufour, S., Robineau, S., Bigay, J., Antonny, B., Chabre, M., and Chardin, P. (1997). Role of protein-phospholipid interactions in the activation of ARFl by the guanine nucleotide exchange factor Arno. J. Biol. Chem. 272, 22221-22226. 

Certain examples illustrate the importance of nonenzymatic binding reactions. These include hemoglobin, protein-phospholipid interactions, and the nonenzymatic binding abilities of proteins, nucleic acids, and mucopolysaccharides. 

New developments in immobilization surfaces have lead to the use of SPR biosensors to monitor protein interactions with lipid surfaces and membrane-associated proteins. Commercially available (BIACORE) hydrophobic and lipophilic sensor surfaces have been designed to create stable membrane surfaces. It has been shown that the hydrophobic sensor surface can be used to form a lipid monolayer (Evans and MacKenzie, 1999). This monolayer surface can be used to monitor protein-lipid interactions. For example, a biosensor was used to examine binding of Src homology 2 domain to phosphoinositides within phospholipid bilayers (Surdo et al., 1999). In addition, a lipophilic sensor surface can be used to capture liposomes and form a lipid bilayer resembling a biological membrane. 

The structures of the various lipoproteins appear to be similar (figs. 20.11 and 20.12). Each of the lipoprotein classes contains a neutral lipid core composed of triacylglycerol and/or cholesteryl ester. Around this core is a coat of protein, phospholipid, and cholesterol, with the polar portions oriented toward the surface of the lipoprotein and the hydro-phobic parts associated with the neutral lipid core. The hydrophilic surface interacts with water in plasma, promoting the solubility of the lipoprotein. 

The spectrin family of proteins, depending on the particular function, has numerous smaller motifs and binding sites for interaction with other proteins. These regions are important, as they are major protein-protein or protein-membrane interaction modules that bind to F-actin, proline-containing ligands, and/or phospholipids. Spectrin and dystrophin/utro-phin have all acquired copies of such domains since their evolution from a-actinin, presumably as a consequence of their more diverse roles in the cell. 

As stated, biological membranes are normally arranged as bilayers. It has, however, been observed that some lipid components of biological membranes spontaneously form non-lamellar phases, including the inverted hexagonal form (Figure 1.9) and cubic phases [101]. The tendency to form such non-lamellar phases is influenced by the type of phospholipid as well as by inserted proteins and peptides. An example of this is the formation of non-lamellar inverted phases by the polypeptide antibiotic Nisin in unsaturated phosphatidylethanolamines [102]. Non-lamellar inverted phase formation can affect the stability of membranes, pore formation, and fusion processes. So-called lipid polymorphism and protein-lipid interactions have been discussed in detail by Epand [103]. 

Because of the unique structure of a lipoid matrix consisting of phospholipids and embedded proteins, the interaction of drag molecules with polar head groups, apolar hydrocarbons, or both, can induce several changes in the membrane. Consequently, the drag behavior is changed (diffusion, accumulation, and conformation) [136]. 

This chapter will not review all of the published studies, but instead will focus on examples of computer simulations of phospholipid membrane systems ranging from simple models through descriptions of lipid and water in full atomic detail to complex membranes containing small solutes, lipids, and proteins. The chapter is aimed at medicinal chemists who are interested in drug-phospholipid interactions. Before discussing the results of different simulations, the currently applied methodologies will briefly be described. 

Transmission of extracellular signals to the cell interior is based on receptor-induced recruitment and assembly of proteins into signaling complexes at the inner leaflet of the plasma membrane. Protein-protein and protein-lipid interactions play a crucial role in the process in which molecular proximity in specially formed membrane subdomains provides the special and temporal constraints that are required for proper signaling. The phospholipid bilayer is not merely a passive hydrophobic medium for this assembly process, but is also a site where the lipid and the protein components are enriched by a dynamic process (see Chapter 5). 

Gutsmann, T., Schromm, A.B., Koch, M.H.J., Kusumoto, S., Fukase, K., Oikawa, M., Seydel, U., Brandenburg, K. Lipopolysaccharide-binding protein-mediated interaction of lipid A from different origin with phospholipid membranes. Phys Chem Chem Phys 2 (2000) 4521—4528. 

Cholesterol and membrane proteins, including structural ones such as glycophorin and myelin basic protein and functional ones such as -ATPase, bacteriorhodopsin, and cytochrome c, are important components of biological membranes. Cholesterol-lipid and a number of protein-lipid interactions have therefore been extensively investigated by vibrational spectroscopy. Interactions of hormones and toxins with phospholipid bilayers were also investigated. 

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