Homology modeling

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Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein (the "template").

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 refers of protein refers
to construct the "to construct the "targettarget" protein from its " protein from its
amino acid sequence and an experimental amino acid sequence and an experimental
three-dimensional structure of a related three-dimensional structure of a related
homologous protein. homologous protein.

3. Homology ModelingHomology Modeling
Homology modeling relies on the Homology modeling relies on the
identification of one or more known protein identification of one or more known protein
structures likely to resemble the structure structures likely to resemble the structure
of the query sequence, and on the of the query sequence, and on the
production of an alignment that maps production of an alignment that maps
residues in the query sequence to residues in the query sequence to
residues in the template sequence. residues in the template sequence.

4. Homology ModelingHomology Modeling
The sequence alignment and template The sequence alignment and template
structure are then used to produce a structure 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 dependent The quality of the homology model is dependent
on the quality of the sequence alignment and on the quality of the sequence alignment and
template structure. The approach can be template structure. The approach can be
complicated by the presence of alignment gaps complicated 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 in structural region present in the target but not in
the templatethe template

6. Steps in Model Production Steps in Model Production
The homology modeling procedure can be The 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 assessment Model assessment

7. Template Selection and Sequence Template Selection and Sequence
AlignmentAlignment
The first two steps are often essentially The first two steps are often essentially
performed together, as the most common performed together, as the most common
methods of identifying templates rely on methods of identifying templates rely on
the production of sequence alignments. the production of sequence alignments.

8. Template Selection and Sequence Template Selection and Sequence
Alignment Alignment
The critical first step in homology modeling is the The critical first step in homology modeling is the
identification of the best template structure, if identification of the best template structure, if
indeed any are available. indeed any are available.
The simplest method of template identification The simplest method of template identification
relies on serial pair wise sequence alignments relies on serial pair wise sequence alignments
aided by database search techniques such as aided 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 are Often several candidate template structures are
identified by these approaches.identified by these approaches.
Therefore, choosing the best template from among Therefore, choosing the best template from among
the candidates is a key step, and can affect the final the 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 the This choice is guided by several factors, such as the
similarity of the query and template sequences, of similarity of the query and template sequences, of
their functions, and of the predicted query and their functions, and of the predicted query and
observed template secondary structures. Perhaps observed template secondary structures. Perhaps
most importantly, the most importantly, the coveragecoverage of the aligned of the aligned
regions: the fraction of the query sequence structure regions: the fraction of the query sequence structure
that can be predicted from the template, and the that can be predicted from the template, and the
plausibility of the resulting model. plausibility of the resulting model.

10. Model Generation Model Generation
Given a template and an alignment, the Given a template and an alignment, the
information contained there in must be information contained there in must be
used to generate a three-dimensional used to generate a three-dimensional
structural model of the target.structural model of the target.

11. Model Assessment Model Assessment
A very extensive model validation report can be A very extensive model validation report can be
obtained using the obtained using the "What Check""What Check" software which software which
is one option of the is one option of the "What If""What If" software package. software package.
 It produces a many page document with It produces a many page document with
extensive analyses of nearly 200 scientific and extensive 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 also is available as a free server; it can also
be used to validate experimentally determined be used to validate experimentally determined
structures of macromolecules.structures of macromolecules.

13. References References
www.cmbi.ru.nl/edu/bioinf4/articles/homologymodelingwww.cmbi.ru.nl/edu/bioinf4/articles/homologymodeling
http://www.cmbi.ru.nl/~hvensela/EGFR-verslag/homology.htmlhttp://www.cmbi.ru.nl/~hvensela/EGFR-verslag/homology.html