Protein pKa calculations

In computational biology, protein pK_a calculations are used to estimate the pK_a values of amino acids as they exist within proteins. These calculations complement the pK_a values reported for amino acids in their free state, and are used frequently within the fields of molecular modeling, structural bioinformatics, and computational biology.

pK_a values of amino acid side chains play an important role in defining the pH-dependent characteristics of a protein. The pH-dependence of the activity displayed by enzymes and the pH-dependence of protein stability, for example, are properties that are determined by the pK_a values of amino acid side chains.

The pK_a values of an amino acid side chain in solution is typically inferred from the pK_a values of model compounds (compounds that are similar to the side chains of amino acids). See Amino acid for the pK_a values of all amino acid side chains inferred in such a way. There are also numerous experimental studies that have yielded such values, for example by use of NMR spectroscopy.

The table below lists the model pK_a values that are often used in a protein pK_a calculation, and contains a third column based on protein studies.

When a protein folds, the titratable amino acids in the protein are transferred from a solution-like environment to an environment determined by the 3-dimensional structure of the protein. For example, in an unfolded protein an aspartic acid typically is in an environment which exposes the titratable side chain to water. When the protein folds the aspartic acid could find itself buried deep in the protein interior with no exposure to solvent.

Furthermore, in the folded protein the aspartic acid will be closer to other titratable groups in the protein and will also interact with permanent charges (e.g. ions) and dipoles in the protein. All of these effects alter the pK_a value of the amino acid side chain, and pK_a calculation methods generally calculate the effect of the protein environment on the model pK_a value of an amino acid side chain.

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