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Homology Modelling
Homology Modelling
MODELLING
Presentor:
Prof. Meet Desai
Dr. Tejas M. Dhameliya M. Pharm Sem I
En. No.
202280822003
Department of Pharmaceutical Chemistry &
Quality Assurance
L. M. College of Pharmacy (228)
Ahmedabad-380009
INTRODUCTION OF HOMOLOGY
MODELLING
• Homology or comparative modeling uses
experimentally determined 3D structure of
another protein that has a similar amino acid
sequence.
• Homology modeling has become a useful tool for
the prediction of protein structure when only
sequence data are available.
• Structural information is often more valuable than
sequence alone for determining protein function.
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/homolo
gy-modeling
• It is based on two major observations:
• (1) Structure of a protein is uniquely
determined by its amino acid sequence,
• (2) during evolution, the structure is more
conserved than the sequence such that similar
sequences adopt practically identical structure
and distantly related sequences show similarity
in folds.
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/homolog
y-modeling
INTRODUCTION TO PROTEIN
STRUCTURE
• Proteins are large, complex molecules exhibit a
remarkable versatility that allows them to
perform a myriad of activities that are
fundamental to life.
• A fundamental principle in all of protein science is
that protein structure leads to protein function.
• The distinctive structures of proteins allow for
the placement of particular chemical groups in
specific places in three-dimensional space.
Structural Bioinformatics, Methods of Biochemical Analysis, Philip E. Bourne Helge
Weissig, Eric D. Scheeff and J. Lynn Fink, Volume 44, Unit 2, pg no:- 16-17.
• Precise placement of chemical groups also allows
proteins to play important structural, transport,
regulatory functions and as a catalyst in organisms.
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/ho
mology-modeling
HISTORY
• The first homology modeling studies were done using
wire and plastic models of bonds and atoms as early
as the 1960’s.
• The models were constructed by taking the
coordinates of a known protein structure and
modified by hand for those amino acids that did not
match the structure.
• In 1969 David Phillips, Brown and co-workers
published the first paper regarding homology
modeling.
https://en.wikipedia.org/wiki/Homology_modeling
STEPS OF HOMOLOGY MODELLING
http://aidanbudd.github.io/ppisnd/trainingMaterial/allegraVia/PPI/tutorial_on_homolog
y_modelling.html
(6)Model optimization
(7)Model validation (by hand or using different
servers)
(8)Iteration to correct mistakes (if any)
http://aidanbudd.github.io/ppisnd/trainingMaterial/allegraVia/PPI/tutorial_on_homology
_modelling.html
STEP 1: TEMPLATE RECOGNITION AND
INITIAL ALIGNMENT
• To identify the template, the program compares
the query sequence to all the sequences of
known structures in the PDB (e.g. BLAST)
• Usually, the template structure with the highest
sequence identity and coverage will be the first
option
• Other considerations:
• conformational state (i.e. active or inactive)
https://microbenotes.com/homology-modeling-working-steps-and-uses
• other molecules or multimeric complexes
• It is possible to choose multiple templates and
build multiple models.
• It is possible to combine multiple templates
into one structure that is used for modeling.
https://microbenotes.com/homology-modeling-working-steps-and-uses
STEP 2: ALIGNMENT CORRECTION
• Having identified one or more possible
modeling templates using the initial screen
described above, more sophisticated methods
are needed to arrive at a better alignment.
https://microbenotes.com/homology-modeling-working-steps-and-uses
STEP 3: BACKBONE GENERATION
• When the alignment is ready, the actual model building
can start.
• Creating the backbone is trivial for most of the model:
one simply transfers the coordinates of those template
residues that show up in the alignment with the model.
• If two aligned residues differ, the backbone coordinates
for N, α-C, C and O and often also the β-C can be copied.
• Conserved residues can be copied completely to provide
an initial guess.
https://microbenotes.com/homology-modeling-working-steps-and-uses
STEP 4: LOOP MODELING
https://microbenotes.com/homology-modeling-working-steps-and-uses
• Changes in loop conformation are notoriously
hard to predict.
• Loop modeling: a search is made through the
PDB for known loops containing endpoints that
match the residues between which the loop is
to be inserted.
https://microbenotes.com/homology-modeling-working-steps-and-uses
STEP 5: SIDE CHAIN MODELING
https://microbenotes.com/homology-modeling-working-steps-and-uses
STEP 6: MODEL OPTIMISATION
https://microbenotes.com/homology-modeling-working-steps-and-uses
• This process is repeated until the solution
converges.
• This boils down to a series of rotamer
prediction and energy minimization steps.
https://microbenotes.com/homology-modeling-working-steps-and-uses
STEP 7: MODEL VALIDATION
https://microbenotes.com/homology-modeling-working-steps-and-uses
• There are two principally different ways to
estimate errors in a structure
– Calculating the model’s energy based on a
force field.
– Determining normality indices that describe
how well a given characteristic of the model
resembles the same characteristic in real
structures.
https://microbenotes.com/homology-modeling-working-steps-and-uses
STEP 8: ITERATION TO CORRECT MISTAKES
https://microbenotes.com/homology-modeling-working-steps-and-uses
USES OF HOMOLOGY MODELLING
• 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
• Because it is difficult and time-consuming to obtain
experimental structures from methods such as X-ray
crystallography and protein NMR for every protein of
interest, homology modeling can provide useful structural
models for generating hypotheses about a protein’s
function.
https://microbenotes.com/homology-modeling-working-steps-and-uses
RECENT APPLICATIONS OF HOMOLOGY
MODELLING
• The Homology model of 17β-HSD2 (17β-
Hydroxysteroid dehydrogenase type 2) in complex
with NAD+ and 17β-estradiol was built, using a
multi-fragment "patchwork" approach.
• The molecular basis and the amino acids involved
in the enzymatic functionality are poorly
understood, as no crystal structure of the
membrane-associated 17β-HSD2 exists.
• The functional properties of only few amino acids
are known.
https://www.sciencedirect.com/science/article/abs/pii/S0960076020303150
• To determine the 17β-HSD2 topology and to
confirm the quality of the model, fifteen
selected amino acids were exchanged one by
one using site directed mutagenesis.
• The mutants’ functional behavior
demonstrated that the generated model was of
very good quality and allowed the identification
of several key amino acids involved in either
ligand or internal structure stabilization.
https://www.sciencedirect.com/science/article/abs/pii/S0960076020303150
RECENT APPLICATIONS OF HOMOLOGY
MODELLING
• The Homology modeling of the 17β-HSD3
membrane-associated enzyme was done to
check the 16-Picolyl-androsterone derivative
inhibitory activity towards the enzyme and
also to check the metabolic stability and
cytotoxic effect on various cancer cells.
https://www.sciencedirect.com/science/article/abs/pii/S096007602100039X
REFERENCES
• https://www.google.com/search?q=homology+m
odelling&source=lnms&tbm=isch&sa=X&ved=2a
hUKEwiv87HVw53wAhV773MBHeAmBVAQ_AUo
AXoECAEQAw&biw=1366&bih=568#imgrc=DeH2
WiBt0aoLfM
• https://www.sciencedirect.com/topics/biochemi
stry-genetics-and-molecular-biology/homology-
modeling
• https://www.nature.com/scitable/topicpage/prot
ein-structure-14122136/#:~:text=Proteins%20are
%20built%20from%20a,acids%20have%20nonpol
ar%20side%20chains
• https://microbenotes.com/homology-modelin
g-working-steps-and-uses
• http://aidanbudd.github.io/ppisnd/trainingMa
terial/allegraVia/PPI/tutorial_on_homology_m
odelling.html
• https://www.sciencedirect.com/science/article
/abs/pii/S096007602100039X
• https://www.sciencedirect.com/science/article
/abs/pii/S0960076020303150
• https://en.wikipedia.org/wiki/Homology_mod
eling
THANK YOU