Conserved structural features on protein surfaces: small exterior hydrophobic clusters.

The extent to which side-chains at the surface of globular proteins adopt well-defined conformations is a matter of some controversy and, in turn, the idea that specific interactions amongst them might make a significant contribution to defining tertiary structures would be generally seen as questionable. In at least some cases, however, there is evidence for organisation of the surface to form discrete, tightly packed clusters. In this paper we examine the role of such clusters in accommodating large, hydrophobic residues on the exterior of protein structures. Taking poplar plastocyanin as a detailed example, we find a variety of ways in which solvent accessibility of such non-polar groups can be limited and we highlight, in particular, a rather simple type of cluster in which a single hydrophobic residue is substantially excluded from solvent by a cage of surrounding, chiefly hydrophilic, side-chains. Comparison with the structures of a number of other proteins which share with plastocyanin the Greek key beta-sandwich topology, but are otherwise unrelated, produces the remarkable finding that analogous clusters are commonly found in the topologically equivalent position. This suggests that these features, which we call small exterior hydrophobic clusters (SEHCs), may have an important structural role and we able that their recurrent position in these proteins is such that they may help to fix the register of non-sequential beta-strands and, perhaps, to specify their association during folding. Similar SEHCs can also be identified in other classes of protein structure and we give a four-helix bundle protein, the rop dimer, as an example. It seems likely that accommodation of large non-polar residues provides a mechanism for introducing a degree of local order in to the surface layers of proteins in solution and it is possible that this behavior could play a role in locking tertiary structures. Thus, while the packing of the hydrophobic core of a globular protein is surely the dominant driving force for folding, it may be that, in some cases at least, interactions among surface residues also play an important role in determining the fine details of the structure.