Homology modelling using Swiss Model

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A Brief description of basics of HOMOLOGY MODELLING

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Homology Modelling using Swiss Model: 

Homology Modelling using Swiss Model Presented By Tanuja . D Asst.professor MS(Pharm)Pharmacoinformatics

CONTENTS: 

Closing remarks CONTENTS Introduction Steps in Homology Modelling Swiss Model Modes of Swiss Model References 2 Homology Modelling Using SWISS MODEL

INTRODUCTION: 

INTRODUCTION Homology modelling, also known as comparative modelling of protein . Refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence. Predicts the three-dimensional structure of a given protein sequence (target) based on an alignment to one or more known protein structures (templates) Evolutionarily related proteins have similar sequences and naturally occurring homologous proteins have similar protein structure 3 Homology Modelling Using SWISS MODEL

PRINCIPLE: 

PRINCIPLE If two proteins share a high sequence similarity, they are likely to have very similar three-dimensional structures. If one of the protein sequences has a known structure, then the structure can be copied to the unknown protein with a high degree of confidence. Repositories-Swiss Model, Protein Model Portal and ModBase 4 Homology Modelling Using SWISS MODEL

STEPS IN HOMOLOGY MODELLING: 

STEPS IN HOMOLOGY MODELLING Template recognition and initial alignment Alignment correction Backbone generation Loop modelling Model refinement Iteration Model validation 5 Homology Modelling Using SWISS MODEL Side chain Modelling

Template Recognition and initial alignment : 

T emplate Recognition and initial alignment Searching the Protein Data Bank (PDB) for homologous proteins with determined structures. A database protein should have at least 30% sequence identity, highest resolution and the most appropriate cofactors for it to be a template sequence. The search can be performed using a heuristic pair wise alignment search program like BLAST or FASTA 6 Homology Modelling Using SWISS MODEL

Alignment correction : 

Alignment correction Dynamic programming methods to search for optimum alignments local or global between a pair of sequences. This approach is useful to search databases for homologous sequences. Multiple sequence alignment methods simultaneously align several sequence to identify conserved regions, predict functional site and protein function. This approach is particularly suited for proteins with low (<40%) sequence identities 7 Homology Modelling Using SWISS MODEL

Backbone generation….: 

Backbone generation …. Once optimal alignment is achieved, the corresponding coordinates residues of the template proteins selected can be simply copied onto the target protein. If multiple templates selected, then average coordinate values of the templates are used. When the alignment is ready, the actual model building can start. 8 Homology Modelling Using SWISS MODEL

Loop Modelling: 

Loop Modelling After the sequence alignment, there are often regions caused by insertions and deletions leads to gaps in sequence alignment. The gaps are modeled by loop modeling, which is a very problem and is also a major source of error. There are three main approaches to loop modeling: Knowledge based Energy based In between or hybrid 9 Homology Modelling Using SWISS MODEL

Side-chain modelling: 

Side-chain modelling After the main chain atoms are built, the positions of side chains should be determined. By searching every possible conformation of Torsion angle which has the lowest interaction energy. When we compare the side-chain conformations (rotamers) -conserved –similar torsion angles 10 Homology Modelling Using SWISS MODEL

Model Refinement: 

Model Refinement Model refinement is done by Molecular Dynamic Simulation. Energy minimization procedure on the entire model, which moves the atoms in such a way that the overall conformation has the lowest energy potential. The goal of energy minimization is to stabilize the structure. 11 Homology Modelling Using SWISS MODEL

Model Validation: 

Model Validation The final model has to be evaluated for checking the φ (phi)–ψ (psi)angles, chirality, bond lengths, close contacts and also the stereo chemical properties. Every homology model contains errors. Various online Protein validation software packages are available. Ex: Procheck ,WHATIF, ANNOLEA ,VERIFY3D ,PROSA 12 Homology Modelling Using SWISS MODEL

Iteration: 

Iteration When errors in the model are recognized and located, they can be corrected by iterating portions of the homology modelling process . Small errors that are introduced can be removed by running a shorter molecular dynamics simulation. Large mistakes in the backbone conformation sometimes require the complete process to be repeated with another alignment or even with a different template . 13 Homology Modelling Using SWISS MODEL

SWISS MODEL SERVER: 

SWISS MODEL SERVER SWISS-MODEL (http://swissmodel.expasy.org) is a server for automated comparative modelling of three-dimensional (3D) protein structures. Web based integrated service for modelling. Swiss Model -Work space a personal web-based area for each user in which protein homology models can be built and the results of completed modelling projects are stored and visualized 14 Homology Modelling Using SWISS MODEL

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2.ALIGNMENT MODE 1.AUTOMATED MODE . 3.PROJECT MODE MODES OF SWISS MODEL 15 Homology Modelling Using SWISS MODEL

Automated mode: 

The "automated mode" is suited for cases where the target-template similarity is sufficiently high to allow for fully automated modelling. Automated sequence alignments are sufficiently reliable when target and template share more than 50% percent of sequence identity. The Submission requires Amino acid Sequence or the UNIPROT Accession Code of Target Protein. Automated mode 16 Homology Modelling Using SWISS MODEL

Alignment mode: 

Alignment mode The "alignment mode" allows the user to test several alternative alignments and evaluate the quality of the resulting models in order to achieve an optimal result. 1. Prepare a multiple sequence alignment 2. Submit your alignment to the Workspace Alignment Mode 3. Select Target and Template 4. Check Alignment and Submit 17 Homology Modelling Using SWISS MODEL

Project Mode: 

Project Mode Project files contain the superposed template structures, and the alignment between the target and template. Project files can be generated inside the program DeepView by the workspace template selection tools, and are also the default output format of the modelling pipeline. 18 Homology Modelling Using SWISS MODEL

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Home page 19 Homology Modelling Using SWISS MODEL

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WorkSpace 20 Homology Modelling Using SWISS MODEL

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Within a few minutes of submission, results are returned to the Workspace. Output Page: The model in pdb format (plus simple viewer) Query to template alignment Simple assessment graphs Logging data of the modeling process Save the model in Swiss- PdbViewer ( DeepView ) Project format, then open in Swiss- PdbViewer . OUT PUT 23 Homology Modelling Using SWISS MODEL

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Homology modelling 24 Homology Modelling Using SWISS MODEL

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CLOSING REMARKS In the absence of experimental structures, homology modeling plays an important role in the drug discovery process. 25 Homology Modelling Using SWISS MODEL

REFERENCES: 

Arnold, K. et al. (2009) The protein model portal. J. Struct . Funct . Genomics. 10, 1–8 Pieper, U. et al. (2006) MODBASE: a database of annotated comparative protein Structure models and associated resources. Nucleic Acids Res. 34 (Database issue), D291–295 Dalton, J.A. and Jackson, R.M. (2007) An evaluation of automated homology modelling methods at low target template sequence similarity. Bioinformatics 23 1901–1908 Fischer, D. (2006) Servers for protein structure prediction. Curr . Opin . Struct . Biol. 16, 178–18 REFERENCES 26 Homology Modelling Using SWISS MODEL

REFERENCES: 

Kairys , V. et al. (2006) Using protein homology models for structure-based studies: approaches to model refinement. Sci. World J. 6, 1542–1554 Marti- Renom , M.A. et al. (2000) Comparative protein structure modeling of genes and genomes. Annu . Rev. Biophys . Biomol . Struct . 29, 291–325 Burley, S.K. et al. (2008) Contributions to the NIH-NIGMS protein structur initiative from the PSI production centers . Structure 16, 5–11 Ginalski , K. (2006) Comparative modeling for protein structure prediction. Curr . Opin . Struct . Biol. 16, 172–177 Larsson, P. et al. (2008) Using multiple templates to improve quality of homology models in automated homology modeling . Protein Sci. 17, 990–1002 Novotny J, Rashin AA, Bruccoleri RE (1988): Criteria that discriminate between native proteins and incorrectly folded models. Proteins 4:19–30. REFERENCES 27 Homology Modelling Using SWISS MODEL

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ACKNOWLEGDEMENT 28 Homology Modelling Using SWISS MODEL

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QUERIES 30 Homology Modelling Using SWISS MODEL