Homology modeling:

Modeller

Michael Dolan
Source: Aza Toth
 What is “molecular modeling?”
• a technique for deriving, representing and manipulating the
structures and reactions of molecules, and those properties
that are dependent on these three dimensional structures

• Drug design
• Protein homology (or comparative) modeling
• Nucleic acid 2º or 3º structure
• Protein folding/threading
• Molecular dynamics protein-centric
• Measurements
 Experimental protein structure
prediction methods
• X-ray Diffraction
– Only a small number of proteins
will crystallize
– A crystal is not the protein’s
native environment
– Very time consuming
Source: http://bit.ly/2k4pgZg
• Nuclear magnetic resonance (NMR)
– generally explores isolated
proteins rather than protein
complexes
– Very time consuming

Source: http://www.langelab.ch.tum.de/
 Why the need for
computational protein
structure prediction?

The number of protein structures solved

so far are fewer than the number of
genes known.
Why the need for computational
protein structure prediction?
 Why the need for computational
protein structure prediction?
• The rate of discovery of new proteins far outweighs our ability
to functionally characterize them
 Why the need for computational
protein structure prediction?

Structures of membrane
proteins, ion channels,
transporters can be large and
difficult to crystallize….
 Computational methods for protein
structure prediction

• Homology (or “comparative”) modeling today

• Fold Recognition / Threading

• ab initio
tomorrow
Protein Structure

D. W. Mount: Bioinformatics, Cold Spring Harbor Laboratory Press, 2001.

 What is homology modeling?
Homology modeling uses homologous sequences with
known 3D structures for the prediction of the structure
of a target sequence

• Proteins sharing a significant similarity of sequence

can be expected to share also a significant similarity
of structure

• Protein tertiary structure is better conserved than

amino acid sequence
Source: https://www.unil.ch/pmf/en/home/menuinst/technologies/homology-modeling.html
Homology modeling workflow
Are there any well characterized proteins similar
Find Template
to my protein?

Align sequences What is the position-by-position

target/template equivalence?

What is the detailed 3D structure of my

Build model protein?

Evaluate model Measure the model quality. Is my model any good?

Limitations of homology modeling

• Accuracy is highly dependent on the sequence

identity between target and templates.

• Important errors can also happen in regions of the

protein that share little sequence identity with the
templates, even though the rest of the protein
exhibits a high sequence identity.

• There are still ~5200 protein families with unknown

structure outside the range of comparative modeling
 Sequence Identity
• 60-100%
– Comparable to medium resolution NMR
– Substrate specificity

• 30-60%
– Molecular replacement in crystallography
– Support site-directed mutagenesis through visualization

• 25- 30%
– May contain serious errors <25% ? Forget about it…
– “twilight zone
I-TASSER
 Protein homology modeling using
Modeller
Dr. Andrej Sali

https://salilab.org/modeller/

Free for academic use

 Homology modeling using Modeller
• Input:
– Alignment between target & template
– Known protein structure of the template

• Output:
– Model for the target
Homology modeling using Modeller
Hands-on Activity: Homology modeling
using Modeller
• Tutorial files: https://shorturl.at/moCS0

• Modeling of Lottia pelta malate

dehydrogenase Modeller using Chimera web
service

• Modeling of S. aureus tyrosine phosphatase

with Modeller using standalone program