Abstract
Experimental characterization and annotation of amino acids belonging to domains of unknown function (DUF) proteins are expensive and time-consuming, which could be complemented by computational methods. Cysteine, being the second most reactive amino acid at the catalytic sites of enzymes, was selected for functional annotation and characterization on DUF proteins. Earlier, we reported functional annotation of cysteine on DUF proteins belonging to the COX-II family. However, holistic characterization of cysteine functions on DUF proteins was not known, to the best of our knowledge. Here, we annotated and characterized cysteine residues based on post-translational modifications (PTMs), biochemical pathways, diseases, taxonomy, and protein microenvironment. The information on uncharacterized DUF proteins was initially obtained from the literature, and the sequence, structure, pathways, taxonomy, and disease information were retrieved from the SCOPe database using DUF IDs. Protein microenvironments (MENV) around cysteine residues from DUF proteins were computed using protein structures (n = 70 342). The cysteine PTMs were predicted using the in-house cysteine-function prediction server, DeepCys https://deepcys.bits-hyderabad.ac.in). The accuracy of the prediction, validated against known experimental cysteine PTMs (n = 18 626), was 0.79. The information was consolidated in the database (https://cysduf.bits-hyderabad.ac.in/), retrievable in downloadable formats (CSV, JSON, or TXT) using the following inputs, DUF ID, PFAM ID, or PDB ID. For the first time, we annotated cysteine PTMs in DUF proteins belonging to seven different biochemical pathways and various species across the taxonomy, notably for the SARS-CoV-2 virus. The nature of MENV around cysteine from DUF proteins was mainly buried and hydrophobic. However, in the SARS-CoV-2 virus, a significant number of functional cysteine residues were exposed on the surface with hydrophilic microenvironment.