Genomics refers to the analysis of genomes and functional genomics is a component of this field that uses varied approaches to understand the biological importance or function of non-coding DNA sequences in genomes. Inspite of the fact that the vast majority of metazoan genome sequences are comprised of non-coding DNA, little is known about the functional or evolutionary constraints that act on these enigmatic sequences [Fields, et al., 1999]. The recent availability of whole-genome sequence data, however, has generated an unprecedented opportunity and challenge to scientific community albeit prediction of molecular function by bioinformatics tools with functionally characterized proteins has become status quo and there is plethora of proteins that has no experimentally determined function. Such predictions are used to obtain a preliminary functional annotation and thereby to guide wet bench experiments.
Genome sequences are used first to predict the set of possible proteins which are compared with all known sequences in central databases. The function of many proteins has already been determined in some organisms and similarity in sequence generally reflects similarity in function [Pellegrini, et al., 1999]. In many Instances there is a reasonable match for half of the proteins with unknown function to a previously sequenced protein from another organism. Genes may show sequence similarity that is limited to a certain region or genes may share high sequence similarity across their entire length. Besides a protein encoded by a gene may share similarity of a well-characterized DNA-binding domain with other proteins, while other parts of the protein may differ [Whisstock, et al., 2003; Domingues, et al., 2003].
The function of a protein is defined by its interactions with other molecules in its environment. The interactions can be either transient, such as protein - protein interactions involved in intracellular signaling, or relatively stable, such as protein - protein, ligand, RNA/DNA interactions. The structural description of these interactions is an important step towards understanding the biochemical, cellular and biological processes. There is a need to integrate structural information gathered at multiple levels of biological hierarchy into a common framework [Russell, et al., 2004]. Therefore recent developments in computational techniques allow structural biology to shift its focus from the structures of individual proteins to function prediction and annotation [Marcotte, et al., 1999].
In the following case study, a protein of unknown function was selected from the existing PDB database for function prediction studies. The prediction of the function of a hypothetical protein, PDB ID: AF1704 (Archaeglobus fulgidus), is carried out utilizing various bioinformatics tools, programs and servers to understand the biochemical and cellular aspects based on residue conservation among similar proteins from multiple alignments, followed by active site detection and docking studies using CASTp (Computed Atlas of Surface Topography of proteins) server and AutoDock software respectively [Edwards, et al., 2003].
References
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Domingues, F.S. and Lengauer T. (2003). Protein function from sequence and structure data. Applied Bioinformatics. 2, 3-12.
Edwards, Y.J. and Cottage, A. (2003). Bioinformatics methods to predict protein structure and function. A practical approach. Molecular Biotechnology. 23, 139-166.
Fields, S., Kohara, Y. and Lockhart, D.J. (1999). Functional genomics. Proceedings of the National Academy of Sciences USA, 96, 8825–8826.
Marcotte, E.M., Pellegrini, M., Ng, H., Rice, D.W., Yeates, T.O. and Eisenberg, D. (1999). Detecting Protein Function and Protein-Protein Interactions from Genome Sequences. Science. 285, 751 – 753.
Pellegrini, M., Marcotte, E., Thompson, M.J., Eisenberg, D. and Yeates, T.O. (1999). Assigning protein functions by comparative genome analysis: protein phylogenetic profiles. Proceedings of the National Academy of Sciences USA, 96, 4285–4288. .Discovery of a Potent Cdk2 Inhibitor with a Novel Binding Mode, Using Virtual Screening and Initial, Structure-Guided Lead Scoping. Bioorganic and Medicinal Chemistry Letters. 17, 3880-3885.
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