OUTLINE

Protein Structures Predicting Secondary Structures Modeling Protein Structures Structure – Function Relationship

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

Protein Structures

Levels of protein structures:– Primary structure– Secondary structure– Tertiary structure– Quaternary structure

Protein Structures

Levels of protein structures:– Primary structure: This is simply the amino acid

sequences of polypeptides chains (proteins).

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.

Protein Structures

Levels of protein structures:– Tertiary structure: Three-dimensional

coordinates of the atoms of a chain

Protein Structures

Levels of protein structures:– Quaternary structure: describes the spatial – packing of several folded polypeptides.

Predicting Secondary Structure

Given the primary structure predict the secondary structure content.

Predicting Secondary Structure

Prediction Methods:– Statistical Methods,– Nearest Neighbors,– Neural Networks,– Support Vector Machines

Modeling Protein Structures

Protein Folding– A protein folds into a unique 3D structure under

the physiological condition,– We want to determine this structure.

Modeling Protein Structures

Protein Folding

Modeling Protein Structures

Methods:– Homology Modeling,– Protein Threading.

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.

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.

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

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.

Modeling Protein Structures

Method 2: Protein Threading– Define and try to minimize an energy function,

Modeling Protein Structures

Method 2: Protein Threading

Modeling Protein Structures

Method 2: Protein Threading

Structure – Function Relationship

Functional Conservation:– Function of a protein depends primarily on its

structure,– Functional regions are usually structurally conserved

Structure – Function Relationship

Protein Databases:– PDB: 3D structures,– SCOP: Classification of proteins

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

Structure – Function Relationship

Find the optimal alignment:

Structure – Function Relationship

Find the optimal alignment:

Structure – Function Relationship

Find the optimal alignment:

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.

Structure – Function Relationship

Find the optimal alignment (Another Method):– DALI:

Structure – Function Relationship

Find the optimal alignment (Another Method):– DALI:

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.