Chemistry Department, Pavia University, Viale Taramelli 12, I-27100 Pavia, Italy
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Globular protein structures are often divided into two regions, the surface, which is in contact with the surrounding molecules, and the interior, which is not accessible to the external molecules. Since most of the surrounding molecules, both
In this article, it is shown that with the use of information published in scientific journals and disseminated in databases, it is easy to give a sound and quantitative framework to a fundamental concept like that of the amino acid polarity/apolarity antinomy.
All textbooks on protein structure and chemistry state that globular proteins are stabilised, in their native and folded state, by the spatial separation of their apolar residues, which cluster in the protein interior, from their polar residues, which are disseminated at the protein surface and are then in contact with the aqueous solution where proteins exist and exert their function. Although not all proteins are globular, for example, membrane or intrinsically disordered proteins, the segregation of polar and apolar residues is one of the major driving forces that allow life to exist. Thanks to that, globular proteins are in fact stable, soluble and functional in an aqueous environment. Their functions, in particular, are generally ensured by the residues that are at their surface and can be accessed not only by water molecules but also by a variety of other molecules, including substrates, inhibitors, cofactors and etc.
Not surprising, a myriad of studies were focused on protein surfaces, including procedures of computational docking, identification of functional protein–protein interfaces and analysis of packing interactions in the solid state[4,5]. A common feature of all these studies is the need of a quantitative criterion to distinguish the two types of amino acid residues, those that are buried in the protein interior and those that are exposed to the solvent. Several pioneering studies were focused on techniques to measure numerically the area of the solvent accessible surface (
Once it is possible to compute the area of the surface accessible to the solvent, the decision whether a residue is exposed to the solvent should be naïve: if the area is larger than 0, the residue is accessible while it is buried in the opposite case. However, the decision is somehow more complex. On the one hand, it is necessary to consider that different residues have different dimensions and so also different
For this reason, different criteria are used by different scientists. For example, according to Levy, an amino acid was considered to be at the protein surface if its relative solvent accessibility was higher than 25%. In this case, the relative solvent accessibility of the
Contrary to the previously mentioned studies, Duarte and colleagues did not use the relative
Obviously, a binary classification in buried/accessible residues might seem rather coarse, since the degree of solvent accessibility of a residue can be a variable, ranging from residues that have very little accessibility, perhaps with only one atom that can be truly solvated by water, to residues that are completely accessible to the solvent and can be surrounded by numerous water molecules. As a consequence, one might prefer a different approach, in which solvent accessibility can be handled as a real, continuous variable. For example, Scherrer and colleagues published a model of sequence evolution that explicitly accounts for the solvent accessibility of each residue in a protein, where the evolutionary rate varies linearly with the solvent accessibility. Also to study the relationship between chemical shifts and atom solvent accessibility, it was necessary to use real
It is evident that some confusion and divergent criteria are routinely used to identify the residues that are at the surface of globular proteins and, in order to try to solve this controversy, it is better to go back to the basic ideas of protein chemistry: the folding of a long polypeptide is mainly dictated by the necessity to segregate most of the apolar residues in the protein interior while keeping most of the polar residue in contact with water. As a consequence, the best
Certainly, it is preferable to use the relative
It is then mandatory to verify if the computations of
Given a certain threshold value for
Figure 1 shows the average hydrophobicity of the protein core and of the protein surface at
Dependence of the average hydrophobicity of the buried and exposed amino acids on the
The difference between the average hydrophobicity of the core and of the surface is depicted in Figure 2, again for proteins containing 100–200 amino acids. The
Relationship between the
The maximal value of
It may appear quite odd that the ranges of
Distribution of the
SASA, solvent accessible surface.
All authors contributed to conception and design, manuscript preparation, read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
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