Solvent Accessibility of Functional Targets in Proteins

Proteins are highly complex, folded polypeptide chains consisting of at least 20 different amino acids that are strung together in unique sequences, which relate to structure and function. Particular amino acids in proteins may be further modified post-translationally to contain a wide variety of covalent modifications normally found in native proteins. The way in which a peptide chain is wrapped and folded governs each amino acid s relative exposure to the outside environment, but post-translational modifications also can obscure the protein surface from easy access to the solvent environment. 

However, just considering the individual properties of each amino acid type is not enough to determine its accessibility to the surrounding aqueous environment. There have been many attempts at developing analytical models with predictive value for determining buried or surface accessible amino acids in a folded polypeptide chain. These studies have concluded fractional assignments for each residue that relate to its accessible surface area (ASA) or its solvent exposed area (SEA). 

Three levels of SEA are presented in the graph for each amino acid, which corresponds to areas in A2 accessible to the solvent environment greater than 30 A2 for highly accessible amino acids, between 10 and 30A2 for medium accessibility, and less than 10 A2 for those residues that are relatively not accessible to the solvent. Only the SEA for each amino acid of 30A2 is shown in the plotted data. The graph shows that the polar amino acids such as serine, threonine, 

The non-polar amino acids glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, and cysteine have lower exposure to the solvent environment than charged or polar residues. However, the frequency at which these groups are found to have an SEA of greater than 30 A2 is much higher than one would expect based solely upon consideration of their hydrophobicity. In fact, nearly 30-50 percent of the time non-polar amino acids in a protein can be found at the surface. 

At the two extremes, lysine is observed as the amino acid most accessible on the surface of proteins while cysteine is the least exposed amino acid. The inaccessibility of cysteine probably stems from the fact that disulfides are typically buried within the polypeptide structure of proteins, whether they are intrachain or interchain in nature, and proteins rarely contain many reduced cysteine thiols. 

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