Theoretical Methods in Protein

Structure Prediction and

Modeling: Unlocking biology’s
storehouse

Presented by: Nikhil S

UM-DAE CBS
Supervised by: Prof.Evans Coutinho
Bombay College of Pharmacy
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 Importance of Protein
structure prediction
Protein Structural diversity : Compare
with nucleic acids
Protein functions
Applications of 3-D structure
Limitations of Experimental methods
X-ray crystallography
Protein NMR
Genome sequencing projects

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 Protein structural hierarchy

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Source: http://www.medchem.umu.se/PDF/Jurgen/proteinstructure.pdf
 Amino acid configuration

Peptide chain as planar structures

ϕ seen along Cα-N bond ψ seen along Cα-Carbonyl bond

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Source: Bruice PY. Organic Chemistry. Prentice Hall; 2014
 Steric clashes

Amino acid residue with various ψ angles with φ = 0˚.

From left to right clashes of O1-H2; O1-O2; O1-C2

Amino acid residue with various φ angles with ψ = 0˚. From left to
right clashes of O1-H2; H1-H2; N1-H2

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Source: Bruice PY. Organic Chemistry. Prentice Hall; 2014
 Ramachandran Plot

From steric clashes to Ramachandran plot

Positions of alpha-helix and beta-sheet ?
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Source: Berg JM, Tymoczko JL, Stryer L. Biochemistry, Fifth Edition,2002
 Protein Secondary structure
Prediction

First step in structure prediction

Empirical statistical methods
Chou-Fasman method
GOR algorithm
Hidden Markov Models
Machine learning algorithms
Support vector machines
Artificial neural networks

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 Chou-Fasman method

Structural propensity based

P(H)
P(E)
P(turn)
Calculation
Ala=2000.Total residues=20000.Helix residues=4000.
Alanine in helix=500
P(H)=p(Ala|Helix)/p(Ala)
p(Ala)=2000/20,000=0.1
p(Ala|Helix)=0.125
Hence P(H)=1.25 8
 Methodology
1. Assign all of the residues the appropriate
set of parameters

T S P T A E L M R S T G
P(H) 69 77 57 69 142 151 121 145 98 77 69 57
P(E) 147 75 55 147 83 37 130 105 93 75 147 75
P(turn) 114 143 152 114 66 74 59 60 95 143 114 156

2. Identify regions where 4/6 have a

P(H)>100 “alpha-helix nucleus”

T S P T A E L M R S T G
P(H) 69 77 57 69 142 151 121 145 98 77 69 57

T S P T A E L M R S T G
P(H) 69 77 57 69 142 151 121 145 98 77 69 57
3. Extend helix in both directions until a set
of four residues have an average P(H)
<100.

T S P T A E L M R S T G
P(H) 69 77 57 69 142 151 121 145 98 77 69 57

Overlapping structures?
Accuracy=50-53%
 GOR Method

Effect of Immediate neighbours

17 amino acid sequence window
Information state function

Secondary structure with highest I value

Accuracy=63%

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 Directional structural
propensities for α-helix

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Source: Garnier J, Osguthorpe DJ, Robson B.1978.
 Hidden Markov Models

Weather model Model for α-helix

Four parameters
Amphiphilic motifs
Accuracy :75%
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Source: Martin J, Gibrat JF, Rodolphe F.2006.
 Support Vector Machines
Classification method
2-D plane:W*X + b = 0
Training with examples
Accuracy close to 75%

Training phase Classification of

unknown protein
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Source: Rivest, R. Chapter 3. Lecture Notes in Machine Learning 1989

 Artificial neural networks

A typical ANN Structure prediction scheme

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Source: Rost B, Sander C.1994.
 Homology modelling

Structure prediction scheme Pseudo energy profile

Similar sequence similar structure
Template recognition and initial alignment
Backbone generation
Loop modelling and Side chain modelling
Model quality assessment and validation 16
Source: Eswar N, Webb B, Marti-renom MA, et al.2007
 Protein threading

Structure prediction scheme

Low homology(<30%)
Structure database
Sequence-structure alignment algorithm
Prediction reliability assessment
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Source: Xu J, Jiao F, Yu L. 2008
 Ab-Initio modelling

Anfinsen’s theory
When is it used?
Potential energy function
Conformational search algorithm
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Source: Dill KA, Chan HS. From Levinthal to pathways to funnels.1997
 Rosetta Energy Function

1) Lennard-Jones Potential
2) implicit solvation model
3) hydrogen bonding
4) electrostatics
5) PDB derived torsion
potentials

Source: Baker D. Protein structure prediction using Rosetta. 2004

 Search Potential Energy Surface

Minimum points on Potential

energy Surface (PES)

Conformational search
techniques

Energy Minimization

Monte Carlo

Molecular Dynamics

Potential energy surface 20

Source: Baker D. Protein structure prediction using Rosetta. 2004
 Clustering

Clusters of decoy structures

Decoys
Energy landscape theory
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Source: Baker D. Protein structure prediction using Rosetta. 2004
 Future perspective

Software that uses a combination of

these method
Algorithms that match a structure with a
library of structural motifs linked with
diverse functions
Large scale docking studies

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