HOMOLOGY MODELLING

PRESENTED BY –

SWARNAVA GHOSH

M.PHARM 2nd SEM

DEPT. – PHARMACEUTICAL CHEMISTRY

SUB – CADD
SUB. CODE- MPC203T
 INTRODUCTION
Homology modeling, also known as comparative modeling, is a
method used to predict the 3D structure of a protein with an
unknown structure by using the known structure of a homologous
protein.
Prediction of the three dimensional structure of a given protein
sequence i.e. target protein from the amino acid sequence of a
homologous protein for which an X-ray or NMR structure based on
an alignment to one or more known protein structures.
If similarity between the target sequence and the template
sequence is detected, structural similarity can be assumed.
In general, 30% sequence identity is
required to generate an useful model.
 Steps in Homology modelling
• Identification and selection of templates
• Sequence similarity, phylogenetic and environmental factors
1 are used.

• Sequence Alignments and Alignment Correction

• Careful inspection and correction of alignments is crucial
2
• Model Building
• There are various methods that can be used in model
3 generation.
 • Loop Modelling
• Accuracy of loop modelling determines the value of the models for
4 further applications

• Side Chain Modelling

• This is usually done by putting side chain onto the backbone.
5

• Model optimization
• The step is done to improve the quality of the model.
6

• Model Validation
• The quality of the model determines the functionality of it.
7
Historical timeline of major developments in homology modeling, taking into consideration the
developments in collective and artificial intelligence fields. CASP: Critical Assessment of protein
Structure Prediction. GPU: Graphics Processing Unit. TPU: Tensor Processing Unit.
Seven classical steps for Homology
Modelling
 SWISS-MODEL
• SWISS-MODEL was the first fully protein homology modelling server
and has been continuously improved during the last 25 years. Its
modelling functionality has been recently extended to include the
modelling homo and heteromeric complexes, given the amino acid
sequences of the interacting partners as starting point. Other
recently introduced features include development new modelling
engine, ProMod3 with increased accuracy of the produced models
and an improved local model quality estimation method based on a
novel version of QMEAN.
• SWISS-MODEL currently generates ∼3000 models a day (∼2 models per minute),
up from ∼1500 models a day in 2014, making it one of the most widely used
structure modelling servers worldwide. Its performance is continuously evaluated
and compared with other state-of-the art servers in the field. To this aim, we are
actively participating to the CAMEO project (Continuous Automated Model
Evaluation, https://cameo3d.org), a fully automated blind prediction assessment
based on weekly pre-release of sequences from the PDB, allowing us to constantly
monitor and improve the performance of the server.
Surface of SWISS-MODEL Template labrary
Rationale for Homology modelling
Structure is more conserved than sequence. This conclusion is supported
by many examples of proteins that have similar structures, yet no
discernable sequence identity. An example is the ftsZ cell division protein
in bacteria which shares structure with mammalian tubulin despite only
12-15% sequence identity. The customary interpretation is that modern
proteins with very similar structures have a common ancestor, and that
their sequences diverged while maintaining the ancestral 3D structure.
• Thus, if the query sequence has significant identity with an empirically
determined protein structure (the template), there is a very high
probability that they have similar structures. Folding the query sequence
identically to the template, guiding the registration by the sequence
alignment, produces a homology model.
Limitations of Homology Modelling
• Cannot study conformational changes
• Cannot find new catalytic/binding sites.
• Brainstorm lack of activity vs activity
 Chymotrypsinogen, trypsinogen and plasminogen
 40% homologus
 2 active, 1 no activity cannot explain.
• Large bias towards structure of template
• Models cannot be docked together
ADVANTAGES:
• It can finds the location of α- carbons of key residues inside
the folded protein.
• It can help to guide the mutagenesis experiments, or
hypothesize structure function relationships.
• The positions of conserved regions of the protein surface can
help identify putative active sites binding pockets and
ligands.
DISADVANTAGES:
• Homology models are unable to predict conformations of
insertions or deletions or side chain positions with a high
level of accuracy.
• Homology models are not useful in modelling and ligand
docking studies necessary for the drug designing and
development process.
 RAMACHANDRAN PLOT
• The Ramachandran plot is a tool used to visualize the dihedral angles of
amino acid residues in a protein structure. It is named after G. N.
Ramachandran, who, along with his colleagues in 1963, analyzed the
allowed regions of φ (phi) and ψ (psi) angles for amino acids in proteins
based on steric constraints and hydrogen bonding patterns.
• In the Ramachandran plot, each point represents a residue in the protein,
with the φ angle on the x-axis and the ψ angle on the y-axis. The plot is
typically divided into regions that correspond to different types of
secondary structure elements, such as α-helices, β-sheets, and turns. The
central region of the plot represents the most favored or allowed
conformations, where steric clashes are minimized and hydrogen bonding is
maximized.
• The Ramachandran plot is a valuable tool for assessing the quality of a
protein structure. Deviations of residues from the allowed regions in the
plot may indicate errors in the structure, such as incorrect backbone
geometry or mis-assigned residue types. High-quality protein structures
usually have a high percentage of residues in the favored regions of the
Ramachandran plot, indicating good stereochemistry and overall structure
quality.
 Applications
• Homology modeling is widely used in structure based drug design process. The importance
of homology modeling is increasing as the number of available crystal structures increases.
There are several other common applications of homology models:
1. studying the effect of mutations;
2. identifying active and binding sites on protein (useful for ligand design);
3. searching for ligands of a given binding site (database mining);
4. designing novel ligands of a given binding site;
5. modeling substrate specificity;
6. predicting antigenic epitopes;
7. protein-protein docking simulations;
8. molecular replacement in X-ray structure refinement;
9. rationalizing known experimental observations and
10. planning new computational experiments with the provided models.
Typical applications of a homology model in drug discovery require a very high accuracy of
the local side chain positions in the binding site. A very large number of homology models
have been built over the years. Targets have included antibodies and many proteins involved
in human biology and medicine.
Applications of homology modelling relevant to ligand design
Applications of structure based homology modelling
 References
• Vyas, V. K., Ukawala, R. D., Ghate, M., & Chintha, C. (2012). Homology modeling a
fast tool for drug discovery: current perspectives. Indian journal of pharmaceutical
sciences, 74(1), 1–17. https://doi.org/10.4103/0250-474X.102537.
• Pawar, S. V., Banini, W. S. K., Shamsuddeen, M. M., Jumah, T. A., Dolling, N. N. O.,
Tiamiyu, A., & Awe, O. I. (2024). Prostruc: an open-source tool for 3D structure
prediction using homology modeling. Frontiers in Chemistry, 12.
https://doi.org/10.3389/fchem.2024.1509407.
• JOUR Homology modeling in the time of collective and artificial intelligence
Hameduh, Tareq Haddad, Yazan Adam, Vojtech Heger, Zbynek 2020/01/01m2020
doi: 10.1016/j.csbj.2020.11.007, Computational and Structural Biotechnology
Journal, https://doi.org/10.1016/j.csbj.2020.11.007.
• Waterhouse, A., Bertoni, M., Bienert, S., Studer, G., Tauriello, G., Gumienny, R., Heer,
F. T., de Beer, T. A. P., Rempfer, C., Bordoli, L., Lepore, R., & Schwede, T. (2018).
SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic
acids research, 46(W1), W296–W303. https://doi.org/10.1093/nar/gky427.
• Muhammed, M. T., & Aki-Yalcin, E. (2019). Homology modeling in drug discovery:
Overview, current applications, and future perspectives. Chemical biology & drug
design, 93(1), 12–20. https://doi.org/10.1111/cbdd.13388.
THANK YOU