Homology modeling

Homology modeling is also known as comparative modeling. It predicts structures of proteins or enzymes based on sequence homology with known structures.

The basic principle of if two proteins share a high sequence similarity, they are likely to have very similar 3D 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.

Basically there are six steps of homology modeling.

1)      Template selection

2)      Alignment  of target and  template  sequences(Sequence Alignment)

3)      Backbone model building

4)      Loop modeling

5)      Side chain refinement

6)      Model  evaluations step

·         Template Selection

This step involves selection of an appropriate template. This step forms the foundation of the rest of the homology modeling process.

The template selection involves searching protein data bank (PDB) for homologous    proteins with known structures. The search can be performed via BLAST and FASTA.

 Sequence alignment

Once the structure with highest sequence similarity is identified as a template, the full length sequence of the template and target proteins need to be realigned using, refined alignment algorithms.

 Backbone Model Building

Once optimal alignment is achieved residues in the coordinates of the regions of the target proteins can assume a similar structure as the template proteins. It means that the coordinates of the corresponding residues of the template proteins can be simply copied on target protein.

 Loop Modeling

During the sequence alignment for modeling there are regions formed by the insertion and deletion s producing gaps in sequence alignment. The gaps cannot be directly modeled, so closing the gaps requires loop modeling. Loops are also known as spare parts that contain library of spare parts. These are basically small nucleotide sequences that are inserted into gaps.
Side chain refinement

There are two methods of side chain refinement.

Psi chain refinement

Once main chain atoms are building the positions of side chains that are not modeled must be determined. A side chain can be build by searching every possible confirmation at every torsion angle of the side chain to select the one that has the lowest interaction energy with the neighboring atoms.

Model refinement using energy  function

In this step potential energy calculations are applied to improve the model. This process is also known as energy minimization step. WE can minimize the total energy to get the stable model. In stable model there are less steric clashes.
Model Evaluation

In this final step we can check the quality of model being evaluated to make sure that the structural features of the model are consistent with the physicochemical rules.