Homology modeling, or comparative modeling, constructs a target protein's three-dimensional structure based on its amino acid sequence and related homologous proteins. The process involves identifying suitable template structures, aligning sequences, generating models, and assessing model quality, making template selection a crucial step for accuracy. Model validation can be performed using specialized software to ensure the reliability of the generated structures.

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.

13. ReferencesReferences
 www.cmbi.ru.nl/edu/bioinf4/articles/homologymwww.cmbi.ru.nl/edu/bioinf4/articles/homologym
 http://www.cmbi.ru.nl/~hvensela/EGFR-verslaghttp://www.cmbi.ru.nl/~hvensela/EGFR-verslag