Bioinformatics

1. Bioinformatics Ayesha M. Khan Spring 2013

2. Secondary Structure Types • Secondary Structure: Local conformation of the polypeptide backbone Limited due to: side chains, peptide bond and hydrogen bonding considerations Main types: • α-helix • β-sheet Less regular but also important: • β-turn • Ω-loop

3. Characteristics • The structure repeats itself every 5.4A along the helix axis • These structures have 3.6 amino acid residues per turn • Rise per residue of 1.5 A • Most abundant helical conformations in proteins and accounts for 32 to 38% of all residues • All the amino acids have negative φ and ψ angles, typical values being -60° and -50° respectively. • The helix can exhibit amphiphillic character i.e. they have a hydrophobic and a hydrophilic face. Consequently, many helices are found on the surface of globular proteins and project their hydrophobic face towards the core and the hydrophilic face towards the solvent. Alpha Helices • Predicted by Linus Pauling in 1951 • Spiral chain amino acids stabilized by hydrogen bonds • Polypeptide backbone follows a helical path

4. Types • A helix can be coiled in two different directions (left and right) • Types other than the α-helix: • 310helices • Short and frequently occur at the termini of regular α-helices • 3 residues per turn and 10 atoms enclosed in a ring formed by each hydrogen bond • π-helices • Stabilized by H-bonds of the i-th residue and with the i+5-th residue ahead. Alpha Helices (contd)

5. Beta strands • Consists of two or more parallel or antiparallel adjacent polypeptide chains arranged in such a way that hydrogen bonds can form between the chains. • Characteristics: • Strands of protein lie adjacent to one another, interacting laterally via hydrogen bonds between carbonyl oxygen and amino H atoms. • Strands may be parallel (N-termini of both strands at the same end) or antiparallel. • Average length of a B-strand is 5-7 residues although they can be from 2 to 11 residues in length.

6. Beta strands-contd. • No. of strands in a sheet ranges from 2 to 10, with 5-6 being common. • Φ, ψ, and ω are -120°, 120° and 180°. • Antiparallel sheets are more stable than parallel ones, which is consistent with the hydrogen bond geometry and the fact that small parallel sheets rarely occur.

7. Other Secondary Structure Elements Loop: • Loop regions occur at the surface of the protein molecule. These are regions of a protein chain that are between α-helices and β–sheets, of various lengths and 3D configurations. Characteristics: • The main chain CO and NH groups of loop regions which generally do not form H-bonds with each other, are exposed to the solvent and can form H-bonds with the water molecules. • Have large quantities of charged and polar hydrophilic residues. • From homologous amino acid sequences, it is found that insertions or deletions of a few residues occur almost only in the loop regions. • It is possible to predict loop regions with higher accuracy than α-helices or β–sheets. Reverse Turns: • H-bond between one main chain carbonyl oxygen to the main chain N-H group 3 residues along the chain.

8. Other Secondary Structure Elements (contd.) β-hairpin: • Turns between β –strands • Length of these regions is 8 residues or less, with 2 residue loops being most common. Coiled Coil: • Consist of two or more right handed α-helices wrapped around each other with a slight left handed superhelical twist

9. Secondary structure prediction Why is secondary structure prediction important? • Prerequisite to model the folding process and also tertiary structure modeling of the protein. • If the secondary structure of a protein is known, it is possible to derive a comparatively small number of possible tertiary (3D) structures using knowledge about the ways that secondary structural elements pack

10. The problem of secondary structure prediction INPUT: Amino acid sequences OUTPUT: Predicted structure A typical protein contains about 32% α-helices, 21%β-sheets, and 47% loops or non-regular structure

11. Knowledge of secondary structure in tertiary structure prediction Question: Is it not possible to model the tertiary structure of a protein from the amino acid sequence alone? Up until now it was impossible but secondary structure features help to do this. It has been observed that peptide regions of up to five residues long having identical amino acid sequences are helical in one structure and a β-strand or a loop in other structures.

12. Secondary structure prediction methods • Early methods • Based on empirically derived residue propensities for different conformational states (statistical methods) • Known as ‘first generation’ of secondary structure prediction • Neural network methods • The information in the database regarding protein primary and secondary structures are used to train the network. The trained network is preserved to predict the structure of new proteins. • Nearest-neighbour method • Nearest-neighbor methods are machine-learning methods that predict secondary structure by identifying sequences of known structure that are similar in sequence to the query sequence. Therefore, these methods are homology-based