Studies of protein‐protein interfaces: A statistical analysis of the hydrophobic effect

Abstract

Data sets of 362 structurally nonredundant protein-protein interfaces and of 57 symmetry-related oligomeric interfaces have been used to explore whether the hydrophobic effect that guides protein folding is also the main driving force for protein-protein associations. The buried nonpolar surface area has been used to measure the hydrophobic effect. Our analysis indicates that, although the hydrophobic effect plays a dominant role in protein-protein binding, it is not as strong as that observed in the interior of protein monomers. Comparison of the interiors of the monomers with those of the interfaces reveals that, in general, the hydrophobic amino acids are more frequent in the interior of the monomers than in the interior of the protein-protein interfaces. On the other hand, a higher proportion of charged and polar residues are buried at the interfaces, suggesting that hydrogen bonds and ion pairs contribute more to the stability of protein binding than to that of protein folding. Moreover, comparison of the interior of the interfaces to protein surfaces indicates that the interfaces are poorer in polarkharged than the surfaces and are richer in hydrophobic residues. The interior of the interfaces appears to constitute a compromise between the stabilization contributed by the hydrophobic effect on the one hand and avoiding patches on the protein surfaces that are too hydrophobic on the other. Such patches would be unfavorable for the unassociated monomers in solution. We conclude that, although the types of interactions are similar between protein-protein interfaces and single-chain proteins overall, the contribution of the hydrophobic effect to protein-protein associations is not as strong as to protein folding. This implies that packing patterns and interatom, or interresidue, pairwise potential functions, derived from monomers, are not ideally suited to predicting and assessing ligand associations or design. These would perform adequately only in cases where the hydrophobic effect at the binding site is substantial.

‘Fixed charge’ chemical derivatization and data dependant multistage tandem mass spectrometry for mapping protein surface residue accessibility

“…The results obtained following CID-MS/MS and -MS 3 of the modified forms of peptide 18-42, (LLKVL-GVNVMLRKIAVAAASKPAVE) containing three lysine residues (resulting in the potential formation of three singly modified peptides (18-42 20 20,30,38 ), further demonstrates the utility of the sulfonium ion derivatization approach for the 'targeted' identification and characterization of modified peptide ions. As shown in Figure 1, two singly modified forms of the 18-42 peptide were observed.…”

“…Once again, the loss of two S(CH 3 ) 2 groups was the dominant fragmentation pathway. The MS 3 spectra shown in Figure 5 were used to assign the sites of modification to the K 20 and K 38 residues for the 18-42 20,38 peptide (Figure 5a ) were also observed in the spectrum from the 18-42 30,38 peptide.…”

“…Finally, Supplemental Figure S2 shows the CID-MS/MS and -MS 3 spectra of the quadruply charged precursor ion of the triply modified 18-42 20,30,38 peptide. MS/MS resulted in the characteristic neutral loss of up to three S(CH 3 ) 2 groups, indicating the presence of three modifications within the peptide, while MS 3 confirmed the identity of the peptide sequence and localization of the modifications on each of the three lysine residues, K 20 , K 30 , and K 38 .…”

Hydrophobic folding units derived from dissimilar monomer structures and their interactions

“…Since in the latter case different chains are involved, one may obtain insight from protein-protein associations to better define hydrophobic folding units and locate potential nucleation sites. Examination of the associations of the hydrophobic folding units illustrates some of the similarities with, and differences from, the protein-protein interfaces we have assembled previously (Tsai et al, 1996(Tsai et al, , 1997. The architectures across the interfaces between the hydrophobic folding units resemble those seen at the protein-protein (subunit) interfaces.…”

Indirect Evidence for Self Association of Muscle Fatty Acid Binding Protein from Locusta migratoria

“…The hydrophobic patches are not related to the sizes of the proteins and only weakly to their non-polar surface fraction [28]. Ala, Lys, and Pro provide the highest contributions to non-polar surface fraction for smaller patches [29]. The contribution of the hydrophobic amino acids becomes more important as the patch size increases.…”