Protein Modelin

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The Outline• Introduction•Comparative Modeling•Conclusion•References

Introduction

3D Structure of ProteinsStudying the 3D

Structure of Proteins

Understanding of Protein

Function

Drug Design Process

•The number of solved 3D structures increases slowly compared to the rate of sequencing DNA.

•Predictive methods have gained much interest.

3D Structure of ProteinsNatural Protein

Structure is guided by:

Laws of PhysicsChemical bonds,

H-bonds, electonic

interactions

Theory of Evolution

Families of similar proteins share

similar sequences,

structure, and often function

Protein Modeling

Protein Modeling Methods

Comparative Modeling

(Homology Modeling or Knowledge-Based

Modeling)

De novo Prediction(Ab initio

Prediction)

Comparative Modeling

The 4 main steps of Comparative Modeling

Comparative Modeling

Identification of Modeling TemplatesAligning the Target Sequence with the Template Sequence

Building the Model

Accessing the Model

Identification of modeling templates

• It requires at least one sequence of known 3D structure with significant similarity to the target sequence.

•BLAST, PSI-BLAST, or HHSearch Programs are used.

Identification of modeling templates

The Reference=

The template with the highest sequence similarity

Maximizing the number of C∞ pairs in the common core while minimizing

their relative mean square deviation

Aligning the target sequence with the template sequence

•Using the best-scoring diagonals obtained by SIM.

•Residues which should not be used for model building will be ignored during the modeling process.

Building the model

•Framework Construction Averaging the position

of each atom in the

target sequence, based on

the location of the

corresponding atoms in the template

Building the model

•Building Non-Conserved Loops

WHY?

The accepted

"spare parts" are

sorted according to their RMSD,

and a C α

 framework based on

the five best fragments

can be added to the

model.

Building the model

•Completing the Backbone

The co-ordinates of each central tri-peptide are then

averaged for each target backbone

atom (N, C, O) and

added to the model.

Building the model

•Adding Side Chains

The number of side

chains that need to be

built is dictated by the degree of sequence

identity between

target and template

sequences

Building the model

•Model Refinement

Idealization of bond geometry and removal of

unfavorable non-bonded contacts

can be performed by

energy minimization

with force fields such as

CHARMM, AMBER or GROMOS.

Accessing the Model

•Removing Errors

PS: Error increases rapidly below 30% sequence similarity.

CONCLUSION

We got to know that

Comparative is more accurate…but requires other

structures to be known.

References• Baker, D.; Sali, A. Protein Structure Prediction and

Structural Genomics. Science 2001, 294, 93-96.

• Fiser, A.; Feig, M.; Brooks, C. L.; Sali, A. Evolution and Physics in Comparative Protein Structure Modeling. Acc. Chem. Res. 2002, 35, 413-421.

• Peitsch ;Guex.,N. Comparative protein modeling. GlaxoWellcome Experimental Research S.A. 16, chemin des Aulx 1228 Plan-les-Ouates / Switzerland.

QUESTIONS AND FEEDBACK

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