Protein lipophilic interactions

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. 

Lipooligosaccharide (LOS) bacterial, 25 498 Lipophilic amphiphiles, 24 154-155 Lipophilic interaction dominated substrate recognition, 16 783-786 Lipophilic moieties, 8 706t Lipopolysaccharides (LPS), 4 706 11 47 BPI protein ability to neutralize, 18 257 peptide and protein binding affinity to, 18 256... 

Figure 2 Role of water molecules in hydrogen bonds (upper part) and lipophilic interactions (lower part). In the unbound state (left side), the polar groups of the ligand and the protein form hydrogen bonds to water molecules. These water molecules are replaced upon complex formation. The hydrogen-bond inventory (total number of hydrogen bonds) does not change. In contrast, the formation of lipophilic contact increases the total number of hydrogen bonds due to the release of water molecules from the unfavorable lipophilic environment.

In agreement with the GRID findings, site-directed mutagenesis experiments demonstrated that lipophilic interactions are extremely important for binding to take place in the enzyme cavity CYP2C9. In turn, flexibility of sidechains modifies the physicochemical enviroment of the cavity, as well as the protein pharmacopho-ric pattern. 

Finally, so-called hydrophobic or lipophilic interactions are often mentioned as additional contribution to protein-ligand interactions. These term s are used to describe the preferential association of nonpolar groups in aqueous solution. It should be emphasized, however, that in contrast to what the name suggests, there is no special hydrophobic force. Instead, one should speak of a hydrophobic effect. As further mentioned below, according to the generally accepted view, it arises primarily from the entropically favorable replacement and release of water molecules (42, 43). The association between the nonpolar surfaces itself is simply based on weak London forces... 

Many protein-ligand complexes are characterized by the presence of both polar and lipophilic interactions. The bound conformation of the ligand is determined by the relative importance of these contributions. An interesting example highlighting several important aspects was recenfly described by Lange and co-workers using the binding of non-peptidic inhibitors to the SH2 domain of src kinase [28]. The inhibitors are essentially tetrapeptide mimetics with tyrosine-phosphate or a... 

Another approach based on statistical analysis of residue-specific protein-ligand interaction terms is named TScore [138[. Here, individual protein-ligand interactions are evaluated for each residue within 8 A around the ligand. Force field-based descriptors are replaced by Chemscore [96] and PLP [139] terms for hydrogen bonds, lipophilicity, and steric contact. Its application to a series of factor Xa inhibitors resulted in a predictive tailored scoring function vdth 52 selected descriptors after PLS analysis q = 0.(>4, r = 0.83). This concept allows a visual interpretation of... 

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