Protein Structures

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.