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Predicting 3D Protein Structure using
Homology Modeling
By: Affan Kayser~ Diadji Wague ~ Hua Yang ~ Jordan Liz ~
Tanjina Nadia ~ Adam Nop ~ Kasarah Allen ~ W. Light A.
City College ~ Bioinformatics workshop
Proteins play an important roles in various diseases.
Through analyzing the properties and characteristics
of proteins, we try to find their involvements in
diseases. Structural analysis of the proteins pave our
ways to find solutions to certain diseases. In order to
analyze proteins which structures haven’t been
determine yet, we use homology modeling to model
proteins by using appropriate templates. MOE will
help us do the homology modeling and be able to
reveal the significances of the proteins in diseases
from their structural analysis.
What is Homology Modeling?
Homology modeling is based on the assumption that, if two proteins have similar
sequences then they will have similar structures. If the sequence identity is
greater than 90% then the predicted structure is practically the same as the
template structure. If the sequence identity is lower than 25% then the
predicted structure is not reliable. If the sequence identity is in the range 50%80% then the homology modeling can generate reliable and informative
structure.
There are many software for homology modeling, the general procedure is:
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Search for the template based on sequence similarity using Blast (an online
software provided by the NCBI database)
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Select the candidate template to make sure the E-value of the sequence
alignment is less than 10-4 and sequence identity is greater than 50%.
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Input the target sequence and the template sequence and structure into
homology modeling software to do modeling, for example SWISS MODEL
(http://swissmodel.expasy.org/SWISS-MODEL.html) ,or MOE.
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Check the accuracy of the generated structure model.
Sequence Alignment
www.chemcomp.com
We are using MOE (molecular operating environment,) to do
the modeling and this software will do all the steps for you when you
input the sequences to be modeled.
 We all found our protein sequences from the NCBI
website and save in FASTA format.
 We copied these sequences to MOE and searched
for appropriate template.
 After sequence alignment, we start to model the
target protein structure based on the template
structure.
 Verify the local geometry of the generated model
using Ramachandran Plot.
Tumor specific alteration of TAL1 occur in
patients with T-Cell Acute Lymphoblastic Leukemia
(T-ALL)
 This alteration is caused by chromosomal
rearrangement
Alteration of TAL1 may lead to leukemogenesis
Related to TAL2 and LYL1. Thus, has an etiologic
role in leukemia
Continue…….
Contain a) amino acid residues 1-331
As products
b) truncated species ( residues 176-331)
Both have 1. basic helix-loop-helix motif; 2.
protein dimerization; 3. DNA-binding domain that
were found in transcription factors
subgroup of bHLH protein which is a
potential mediator of T-cell leukemogenesis
PDB ID: 1MDY: As template
TAL1 polypeptides do not
have intrinsic DNA binding
activity
Loop
Beta
 can’t self-associate to form
bHLH homodimers
Helix
May be able to interact with
other bHLH protein in a
stable manner
Two heterodimers(TAL1E12 , TAL1-E47) that
recognize E-box motif
E-box motif: a element found
in various eukaryotic
transcription enhancers
 structure model by MOE
Ramachandran Plot
It is a way to visualize dihedral angles φ against ψ of
amino acid residues in protein structure
 Psoriasis is an inflammatory disease of the
skin and joints
 JunB is an element of the AP-1
transcription factor and is known to
coordinate cell differentiation, stress
responses, cytokine expression in various
organs and proliferation. But when a person
develops psoriasis, the expression levels of
JunB lessen.
The structure of.
CAG33122 protein using
MOE, PDB: 1UAX
This is the HIF1 protein structure done
by MOE homology modeling.
The PBD code: 1P97
Protein analysis of HIF1
The predicted structure on the previous page
displays the HIF1 protein, which is the main
regulator of hypoxia-induced gene expression as
well as the DNA binding protein. It is a
heterodimeric transcription factor composed of
HIF1A.
The HIF1 protein expressed by the structure
concludes that it plays a big role in hypoxia.
However, even though many proteins are known,
this protein helps identify what hypoxia is really
about since it does associate with the HIF1A gene.
1AQN- Structure modeled by
MOE
Acts as an Intramolecular Chaperone
Subtilisin-like serine Proteinase
It facilitates folding by acting as a template for
its protease domain, which does not form A
part of it.
 There are two Subtilisin
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Altered and wild type Subtilisin
They have identical amino-acid sequences
Differs in thermostability and substrate specificities.
Through a mutated intramoleculer chaperone:
•An identical polypeptide can fold into an
altered conformation
•It also maintains memory of the folding
process.
LDLR Structure
•This is the back bone to
• This structure was
created by Moe. It’s the structure of the LDL
the template for the receptor protein.
LDLR protein.
Space Filling Model
• Space filling molecular
models show the relative
atomic sizes of the atoms of
the molecule.
• This model shows the
carbons (gray), hydrogen's
(light gray), oxygen (blue),
carbon monoxide's (red),
and sulfur (yellow) of the
protein.
LDL Receptor
• Knowing the structure of the LDL
receptor scientists can better
understand the effects it has on
Familial Hypercholesterolemia patients.
• For example, scientist can find why the
LDL receptor fails to activate and bind
to the surface and can learn how to
provide LDL receptors to FH patients.
 HER4 , also known as ErbB4, is able to lower the
expression level of breast and prostate tumors.
 ErbB4 is a transmembrane receptor, which is a
protein that covers the plasma membrane of the cell,
that controls cell reproduction and differentiation.
 It is apart of the HER family.
 Has to be enzymatically separated which may change
the function of its Intercellular Domain(ICD) as
stated in several reports
ABG35747 – HER4 MOE
Structure
The predicted structures of our target
proteins help us analyze the
significances of the proteins and its
involvements in diseases. Thus, we have
better understandings of the diseases.
We will continue to create models of
unstructured proteins using modeling
softwares other then MOE to see if they
yield similar results.
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References
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http://www.epitomics.com/products/1200-1.htm
lhttp://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=66393602
http://www.ncbi.nlm.nih.gov/BLAST/Blast.cgiR
http://breast-cancer-research.com/content/8/2/R19
http://www.findarticles.com/p/articles/mi_m0DFY/is_03_2001/ai_70738971
MOE- Molecular Operating Environment
http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=31077211
http://www.wrongdiagnosis.com/medical/hif1_protein.htm
http://www.genecards.org/cgi-bin/carddisp.pl?gene=HIF1A
Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42
MAPK and NF-kappaB.
Frede S, Stockmann C, Freitag P, Fandrey J.
Wegele H, Muller L, Buchner J. (2004). Hsp70 and Hsp90 - a relay team for protein folding.
Rev Physiol Biochem Pharmacol 151:1-44
uhttp://www.ncbi.nlm.nih.gov/BLAST/Blast.cgi
uhttp://www.ebi.ac.uk/cgi-bin/clustalw/result?tool=clustalw&jobid=clustalw-2006080916204016&treendisp=hide&treetype=new&sortby=seqno&color=yes
uhttp://www.ncbi.nlm.nih.gov/gquery/gquery.fcgi
uhttp://ad2004.com/Biblecodes/Hebrewmatrix/leukemia.html
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http://www.humpath.com/IMG/jpg/psoriasis_nail_20xpasd-2.jpg
http://www.nature.com/nature/journal/v437/n7057/full/nature03963.html
http://www.nycornell.org/dermatology/research/img/psoriasis.jpg
http://www.chemcomp.com/software-pro.htm
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Dr. Sat Bhattacharya
Dr. Yuying Q. Gosser
Joe Wu
Harlem Children Society
Bioinformatics workshop at City College
of New York