Computational prediction of eukaryotic phosphorylation sites

Motivation: Kinase-mediated phosphorylation is the central mechanism of post-translational modification to regulate cellular responses and phenotypes. Signaling defects associated with protein phosphorylation are linked to many diseases, particularly cancer. Characterizing protein kinases and their substrates enhances our ability to understand and treat such diseases and broadens our knowledge of signaling networks in general. While most or all protein kinases have been identified in well-studied eukaryotes, the sites that they phosphorylate have been only partially elucidated. Experimental methods for identifying phosphorylation sites are resource intensive, so the ability to computationally predict potential sites has considerable value. Results: Many computational techniques for phosphorylation site prediction have been proposed, most of which are available on the web. These techniques differ in several ways, including the machine learning technique used; the amount of sequence information used; whether or not structural information is used in addition to sequence information; whether predictions are made for specific kinases or for kinases in general; and sources of training and testing data. This review summarizes, categorizes and compares the available methods for phosphorylation site prediction, and provides an overview of the challenges that are faced when designing predictors and how they have been addressed. It should therefore be useful both for those wishing to choose a phosphorylation site predictor for their particular biological application, and for those attempting to improve upon established techniques in the future.