Interdiscip Sci Comput Life Sci (2010) 2: 347–366 DOI: 10.1007/s12539-010-0045-6 Structural Bioinformatics: Deriving Biological Insights from Protein Structures Nagasuma CHANDRA * , Praveen ANAND, Kalidas YETURU (Bioinformatics Centre, Indian Institute of Science, Bangalore 560012, India) Received 23 April 2010 / Revised 18 June 2010 / Accepted 21 June 2010 Abstract: Structural bioinformatics can be described as an approach that will help decipher biological insights from protein structures. As an important component of structural biology, this area promises to provide a high resolution understanding of biology by assisting comprehension and interpretation of a large amount of structural data. Biological function of protein molecules can be inferred from their three-dimensional structures by comparing structures, classifying them and transferring function from a related protein or family. It is well known now that the structure space of protein molecules is more conserved than the sequence space, making it important to seek functional associations at the structural level. An added advantage of structural bioinformatics over simpler sequence-based methods is that the former also provides ultimate insights into the mechanisms by which various biological events take place. A bird’s eye-view of the different aspects of structural bioinformatics is given here along with various recent advances in the area including how knowledge obtained from structural bioinformatics can be applied in drug discovery. Key words: protein structures, structural genomics, structure-function relationship, structural analysis, biological data mining. 1 Introduction Deciphering complete genome sequences of several organisms including that of the human genome, has been marking defining moment in the history of biology (Fleischmann et al., 1995; Forster and Church, 2006; Venter et al., 2001). With the architectural blue-print of life of several different organisms in hand, the next step is to comprehend the huge pool of data (Kyrpides, 1999; Liolios et al., 2008), identify and understand the function of the individual gene products. In biology, knowledge available for one system heav- ily influences understanding of a related system. It is quite understandable therefore, why recognizing simi- larities and deriving relationships are crucial for all fur- ther knowledge, making bioinformatics an integral and important component of modern biology. This need is not only heightened, but is also rendered with the large number of genomes sequenced in the last few years. Where available, protein structures provide much bet- ter functional insight than their sequences alone. The reasons are that: as compared to the sequences, two- fold structures provide (a) a much higher resolution of information about the protein molecules and (b) a * Corresponding author. E-mail: nchandra@serc.iisc.ernet.in much more sensitive approach for detecting similarities among proteins. This is because protein structures are seen to cluster only into certain regions of the entire fold space suggesting that the same fold is repeatedly sampled in nature (Holm and Sander, 1996; Russell et al., 1997). The need to navigate and comprehend this large re- source of experimental and theoretical structural data, has automatically led to genesis of a new discipline called structural bioinformatics (Burley, 2000; Bourne and Weissig, 2008), which has become well established in the last decade. Structural Bioinformatics is prob- ably the best thought of as the discipline, which ra- tionalizes and classifies information contained in the three-dimensional structures of molecules, in terms of their functional capabilities. This ultimately helps us to understand at atomic-level detail, how biological or- ganisms encode, make use of, and pass on information. The main advantages these methods have over simpler sequence-based methods are that they help associate a molecule with a function, and also provide ultimate in- sights into the mechanisms by which various biological events take place. In principle, the term ‘structural bioinformatics’ could encompass all biological macromolecules, but is used here predominantly in the context of protein