1. Protein Structures

2. OUTLINE Protein Structures Predicting Secondary Structures
Modeling Protein Structures
Structure – Function Relationship

3. Protein Structures Why Protein Structures ?
Proteins perform a variety of biological tasks,
Protein structure determines its function,
Protein structure is more conserved than protein sequence, and more closely related to function.
Sequence  Structure  Function

4. Protein Structures Levels of protein structures: Primary structure
Secondary structure
Tertiary structure
Quaternary structure

5. Protein Structures Levels of protein structures:
Primary structure: This is simply the amino acid sequences of polypeptides chains (proteins).

6. Protein Structures Levels of protein structures:
Secondary structure: Local organization of protein backbone: α-helix, β-strand (groups of β-strands assemble into β-sheet), turn and interconnecting loop.

7. Protein Structures Levels of protein structures:
Tertiary structure: Three-dimensional coordinates of the atoms of a chain

8. Protein Structures Levels of protein structures:
Quaternary structure: describes the spatial
packing of several folded polypeptides.

9. Predicting Secondary Structure
Given the primary structure predict the secondary structure content.

10. Predicting Secondary Structure
Prediction Methods:
Statistical Methods,
Nearest Neighbors,
Neural Networks,
Support Vector Machines

11. Modeling Protein Structures
Protein Folding
A protein folds into a unique 3D structure under the physiological condition,
We want to determine this structure.

12. Modeling Protein Structures
Protein Folding

13. Modeling Protein Structures
Methods:
Homology Modeling,
Protein Threading.

14. Modeling Protein Structures
Method 1 Homology Modeling Steps:
Identify a set of template proteins (with known structures) related to the target protein. This is based on sequence homology (BLAST, FASTA) with sequence identity of 30% or more.
Align the target sequence with the template proteins. This is based on multiple alignment. Identify conserved regions.

15. Modeling Protein Structures
Method 1 Homology Modeling Steps:
Build a model of the protein backbone, taking the backbone of the template structures (conserved regions) as a model.
Model the loops. In regions with gaps, use a loop-modeling procedure to substitute segments of appropriate length.
Add sidechains to the model backbone.
Evaluate and optimize entire structure.

16. Modeling Protein Structures
Method 2: Protein Threading
The number of unique structural (domain) folds in nature is fairly small (possibly a few thousand),
Thread (align or place) a query protein sequence onto a template structure in “optimal” way

17. Modeling Protein Structures
Method 2: Protein Threading
Threading: Given a sequence, and a fold (template), compute the optimal alignment score between the sequence and the fold.
If we can solve the above problem, then
Given a sequence, we can try each known fold, and find the best fold that fits this sequence.
Because there are only a few thousands folds, we can find the correct fold for the given sequence.

18. Modeling Protein Structures
Method 2: Protein Threading
Define and try to minimize an energy function,

19. Modeling Protein Structures
Method 2: Protein Threading

20. Modeling Protein Structures
Method 2: Protein Threading

21. Structure – Function Relationship
Functional Conservation:
Function of a protein depends primarily on its structure,
Functional regions are usually structurally conserved

22. Structure – Function Relationship
Protein Databases:
PDB: 3D structures,
SCOP: Classification of proteins

23. Structure – Function Relationship
How to compare protein structures:
find an optimal correspondence between the arrangements of atoms in two molecular structures (say A and B) in order to align them in 3D,
Optimality of the alignment is determined using a root mean square measure of the distances between corresponding atoms in the two molecules

24. Structure – Function Relationship
Find the optimal alignment:

25. Structure – Function Relationship
Find the optimal alignment:

26. Structure – Function Relationship
Find the optimal alignment:

27. Structure – Function Relationship
Find the optimal alignment (Another Method):
DALI:
similar 3D structures have similar intra-molecular distances,
Represent each protein as a 2D matrix storing intra-molecular distance,
Place one matrix on top of another and slide vertically and horizontally – until a common the sub-matrix with the best match is found.

28. Structure – Function Relationship
Find the optimal alignment (Another Method):
DALI:

29. Structure – Function Relationship
Find the optimal alignment (Another Method):
DALI:

30. References
M. Zvelebil, J. O. Baum, “Understanding Bioinformatics”, 2008, Garland Science
Andreas D. Baxevanis, B.F. Francis Ouellette, “Bioinformatics: A practical guide to the analysis of genes and proteins”, 2001, Wiley.
Barbara Resch, “Hidden Markov Models - A Tutorial for the Course Computational Intelligence”, 2010.
Wang, Z., Zhang, L., Sagotsky, J., Deisboeck. T. S. (2007), Simulating non-small cell lung cancer with a multiscale agent-based model, Theoretical Biology & Medical Modelling.