Def-
Homology modeling method for predicting the three-dimensional structure of a protein based on
homology by assigning the structure of an unknown protein using an existing homologous
protein structure as a template.
OR
Homology modeling predicts protein structures based on sequence homology with known
structure.
- It is also known as comparative modeling.
Principle:-
The principle behind it is that if two proteins share a high enough 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. Homology modeling produces an all-atom model based on alignment with
template proteins.
Steps Homology modeling:-
The overall homology modeling procedure consists of six steps.
1. Template selection (BLAST and FASTA)
2. Sequence alignment (T-coffee and PRALINE)
3. Model building (CODA)
(a) Backbone model building
(b) Loop modeling
4. Side chain refinement (SCWRL)
5. Model refinement using energy function (GROMOS)
6. Model evalution (PROCHECK & WHAT IF)
1. Template selection:-
- The first step in protein structural modeling is to select appropriate structural templates.
- This forms the foundation for rest of the modeling process.
- The template selection involves searching the Protein Data Bank (PDB) for homologous
proteins with determined structures.
- The search can be performed using a heuristic pairwise alignment search program such
as BLAST or FASTA.
2. Sequence alignment:-
- Once the structure with the highest sequence similarity is identified as a template, the
full-length sequences of the template and target proteins need to be realigned using
refined alignment algorithms to obtain optimal alignment.
- The best possible multiple alignment algorithms, such as Praline and T-Coffee.
3. Model building:-
- Once optimal alignment is achieved, residues in the aligned regions of the target protein
can assume a similar structure as the template proteins, meaning that the coordinates of
the corresponding residues of the template proteins can be simply copied onto the target
protein
(a) Backbone modeling-it is simplest to use only one template structure.
(b) Loop Modeling- In the sequence alignment for modeling, there are often regions
caused by insertions and deletions producing gaps in sequence alignment.
The following are specialized programs for loop modeling. FREAD, PETRA, CODA,
PETRA.
4. Side chain refinement:-
- Once main chain atoms are built, the positions of side chains that are not modeled must
be determined.
- Modeling side chain geometry is very important in evaluating protein–ligand interactions
at active sites and protein–protein interactions at the contact interface.
- A specialized side chain modeling program that has reasonably good performance is
SCWRL (sidechain placement with a rotamer library; www.fccc.edu/research/labs/
dunbrack/scwrl/)
5. Model refinement using energy function:-
- In these loop modeling and side chain modeling steps, potential energy calculations are
applied to improve the model
- Molecular dynamic tools- GROMOS (www.igc.ethz.ch/gromos/)
6. Model evolution:-
- The final homology model has to be evaluated to make sure that the structural features of
the model are consistent with the physicochemical rules.
- Procheck (www.biochem.ucl.ac.uk/∼roman/procheck/procheck.html)
Uses:-
Uses of Homology Modeling
Protein modeling Provide a solid basis for:
Rational design of proteins with increased stability or novel functions
Analysis of protein function, interactions, antigenic behavior
Structure-based drug design
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