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Homology modeling
- 1. Homology ModelingHomology Modeling Syed M TouseefSyed M Touseef Department of BiotechnologyDepartment of Biotechnology
- 2. Homology ModelingHomology Modeling Homology modelingHomology modeling, also known as, also known as comparative modelingcomparative modeling of protein refersof protein refers to construct the "to construct the "targettarget" protein from its" protein from its amino acid sequence and an experimentalamino acid sequence and an experimental three-dimensional structure of a relatedthree-dimensional structure of a related homologous protein.homologous protein.
- 3. Homology ModelingHomology Modeling Homology modeling relies on theHomology modeling relies on the identification of one or more known proteinidentification of one or more known protein structures likely to resemble the structurestructures likely to resemble the structure of the query sequence, and on theof the query sequence, and on the production of an alignment that mapsproduction of an alignment that maps residues in the query sequence toresidues in the query sequence to residues in the template sequence.residues in the template sequence.
- 4. Homology ModelingHomology Modeling The sequence alignment and templateThe sequence alignment and template structure are then used to produce astructure are then used to produce a structural model of the target.structural model of the target.
- 5. Homology ModelingHomology Modeling The quality of the homology model is dependentThe quality of the homology model is dependent on the quality of the sequence alignment andon the quality of the sequence alignment and template structure. The approach can betemplate structure. The approach can be complicated by the presence of alignment gapscomplicated by the presence of alignment gaps (commonly called indels) that indicate a(commonly called indels) that indicate a structural region present in the target but not instructural region present in the target but not in the templatethe template
- 6. Steps in Model ProductionSteps in Model Production The homology modeling procedure can beThe homology modeling procedure can be broken down into four sequential steps:broken down into four sequential steps: Template selectionTemplate selection Target-template alignmentTarget-template alignment Model constructionModel construction Model assessmentModel assessment
- 7. Template Selection and SequenceTemplate Selection and Sequence AlignmentAlignment The first two steps are often essentiallyThe first two steps are often essentially performed together, as the most commonperformed together, as the most common methods of identifying templates rely onmethods of identifying templates rely on the production of sequence alignments.the production of sequence alignments.
- 8. Template Selection and SequenceTemplate Selection and Sequence AlignmentAlignment The critical first step in homology modeling is theThe critical first step in homology modeling is the identification of the best template structure, ifidentification of the best template structure, if indeed any are available.indeed any are available. The simplest method of template identificationThe simplest method of template identification relies on serial pair wise sequence alignmentsrelies on serial pair wise sequence alignments aided by database search techniques such asaided by database search techniques such as FASTA and BLAST.FASTA and BLAST.
- 9. Selection of Best TemplateSelection of Best Template Often several candidate template structures areOften several candidate template structures are identified by these approaches.identified by these approaches. Therefore, choosing the best template from amongTherefore, choosing the best template from among the candidates is a key step, and can affect the finalthe candidates is a key step, and can affect the final accuracy of the structure significantly.accuracy of the structure significantly. This choice is guided by several factors, such as theThis choice is guided by several factors, such as the similarity of the query and template sequences, ofsimilarity of the query and template sequences, of their functions, and of the predicted query andtheir functions, and of the predicted query and observed template secondary structures. Perhapsobserved template secondary structures. Perhaps most importantly, themost importantly, the coveragecoverage of the alignedof the aligned regions: the fraction of the query sequence structureregions: the fraction of the query sequence structure that can be predicted from the template, and thethat can be predicted from the template, and the plausibility of the resulting model.plausibility of the resulting model.
- 10. Model GenerationModel Generation Given a template and an alignment, theGiven a template and an alignment, the information contained there in must beinformation contained there in must be used to generate a three-dimensionalused to generate a three-dimensional structural model of the target.structural model of the target.
- 11. Model AssessmentModel Assessment A very extensive model validation report can beA very extensive model validation report can be obtained using theobtained using the "What Check""What Check" software whichsoftware which is one option of theis one option of the "What If""What If" software package.software package. It produces a many page document withIt produces a many page document with extensive analyses of nearly 200 scientific andextensive analyses of nearly 200 scientific and administrative aspects of the model.administrative aspects of the model. "What"What Check"Check" is available as a free server; it can alsois available as a free server; it can also be used to validate experimentally determinedbe used to validate experimentally determined structures of macromolecules.structures of macromolecules.