Protein tertiary and quaternary structure determination using Bio informatics tools Dipankar Sarkar 2003CS10161 Group #1
Introduction <ul><li>What is a protein? </li></ul><ul><ul><li>A protein (from the Greek protas meaning of primary importance) is a complex, high-molecular-weight, organic compound that consists of amino acids joined by peptide bonds. </li></ul></ul><ul><li>Proteins are essential to the structure and function of all living cells and viruses. </li></ul>
Protein – Component & synthesis <ul><li>Proteins are polymers built from 20 different L-alpha-amino acids. Proteins are assembled from amino acids using information present in genes. Genes are transcribed into RNA, RNA is then subject to post-transcriptional modification and control, resulting in a mature mRNA that undergoes translation into a protein. mRNA is translated by ribosomes that match the three-base codons of the mRNA to the three-base anti-codons of the appropriate tRNA. The enzyme aminoacyl tRNA synthetase catalyzes the formation of covalent peptide bonds between amino acids forming the protein. </li></ul><ul><li>The two ends of the amino acid chain are referred to as the carboxy terminus (C-terminus) and the amino terminus (N-terminus) based on the nature of the free group on each extremity. </li></ul>
Protein - structure <ul><li>Primary - amino acid sequence </li></ul><ul><li>Secondary - highly patterned sub-structures </li></ul><ul><li>Tertiary - the overall shape of a single protein molecule </li></ul><ul><li>Quaternary - the shape or structure that results from the union of more than one protein molecule </li></ul>
Tertiary structure prediction <ul><li>Aim is of determining the three-dimensional structure of proteins from their amino acid sequences </li></ul><ul><li>There are two methods of structure prediction </li></ul><ul><ul><li>De novo protein modeling – Brute force method of predicting the 3D structure of the protein. Needs a lot of computational power. Example – Rosetta. </li></ul></ul>
Tertiary - Continued <ul><ul><li>Comparative protein modeling – It uses previously solved structures as starting points, or templates. This is effective because it appears that although the number of actual proteins is vast, there is a limited set of tertiary structural motifs to which most proteins belong. Into 2 more types of modeling : </li></ul></ul><ul><ul><ul><li>Homology modelling </li></ul></ul></ul><ul><ul><ul><li>Protein threading </li></ul></ul></ul>
Quaternary structure prediction <ul><li>In addition to the tertiary structure of the subunits, multiple-subunit proteins possess a quaternary structure, which is the arrangement into which the subunits assemble </li></ul><ul><li>There are 3 primary methods of predicting protein-protein interaction </li></ul><ul><ul><li>Phylogenetic distance and co-evolution of interacting domains – Example – ADVICE </li></ul></ul>
Quaternary - Continued <ul><ul><li>Identification of homologous interacting pairs – This method consists of searching whether the two sequences have homologues which form a complex in a database of known structures of complexes. Example :- InterPreTS (Interaction Prediction through Tertiary Structure) </li></ul></ul><ul><ul><li>Identification of structural patterns (target must be a structure) – The third method builds a library of known protein-protein interfaces from the Protein Data Bank. The sequences in the library are then clustered based on structural alignment and redundant sequences are eliminated. Example :- PRISM </li></ul></ul>
Conclusion <ul><li>Methods used by bioinformatics tools are heavily based on algorithmic research, a key area of computer science research. </li></ul><ul><li>As structure prediction is composed of NP hard sub-problems, techniques like neural networks and approximation algorithms are heavily used in the bioinformatics tools. </li></ul>
Bibliography <ul><li>Simons, K. T., Bonneau, R., Ruczinski, I., Baker, D.,(1999) Ab initio protein structure prediction of CASP III targets using ROSETTA, Proteins Suppl 3, 171-6. </li></ul><ul><li>Bates, P.A., Kelley, L.A., MacCallum, R.M. and Sternberg, M.J.E., (2001) Enhancement of Protein Modelling by Human Intervention in Applying the Automatic Programs 3D-JIGSAW and 3D-PSSM., Proteins: Structure, Function and Genetics, Suppl 5:39-46. </li></ul><ul><li>Tan S.H., Zhang Z., Ng S.K.,(2004) ADVICE: Automated Detection and Validation of Interaction by Co-Evolution.. Nucl. Ac. Res., 32 (Web Server issue):W69-72. </li></ul><ul><li>Aloy P.,Russell R.B, InterPreTS: Protein Interaction Prediction through Tertiary Structure., Bioinformatics, 19 (1), 161-162. </li></ul><ul><li>Ogmen U., Keskin O., Aytuna A.S., Nussinov R. and Gursoy A,(2005) PRISM: protein interactions by structural matching., Nucl. Ac. Res.,33 (Web Server issue):W331-336. </li></ul><ul><li>Wikipedia, http://www.wikipedia.com. </li></ul>
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