Study of Loop Length & Residue Composition of β-Hairpin Motif

1. Study of Loop Length & Residue Composition of β-Hairpin Motif Xin Zhan Nov 27, 2006 CS 882 course project

2. Outline • Research background about β-hairpin motif • My task overview • Preliminary results • Future works CS 882 course project

3. β-Hairpin Motif • Simplest protein motif involving two beta strands [from Wikipedia] • adjacent in primary sequence • antiparallel • linked by a short loop • As isolated ribbon or part of betasheet • a special case of a turn • direction of protein backbone reverses • flanking secondary structure elements interact (hydrogen bonds) CS 882 course project

4. Types of Turns • β-turn (most common) • donor and acceptor residues of hydrogen bonds are separated by 3 residues (ii +3 H-bonding) • δ-turn • ii +1 H-bonding • γ-turn • ii +2 H-bonding • α-turn • ii +4 H-bonding • π-turn • ii +5 H-bonding • ω-loop • a longer loop with no internal hydrogen bonding CS 882 course project

5. Loop Length of β-Hairpin • 70% hairpins with loop length ≤7 • Most are 2 residues loops • 2 residues loops prefer type I’ and II’ beta turns [Sibanda & Thornton 85’] CS 882 course project

6. Turn Type of Two residue β-Hairpin (1) • Types I‘ • Residue 1 adopts left-handed alpha-helical conformation • Preference for GLY, ASP, ASN • Residue 2 nearly always GLY • Type II’ • Residue 1 only GLY • Residue 2 polar amino acids such as SER, THR CS 882 course project

7. Turn Type of Two residue β-Hairpin (2) • Residue 2 in type I’ and residue 1 in type II’ has a conformation which can only be adopted by GLY • phi and psi angles are well outside the allowed regions of the Ramachandran plot for amino acids with side chains CS 882 course project

8. Three Residue β-Hairpin • 1st residue adopts right-handed alpha-helical conformation • 2nd in the region between alpha-helix and beta-sheet • 3rd position prefer GLY, ASN, ASP CS 882 course project

9. Four Residue β-Hairpin • 1st and 2nd residues adopting the alpha-helical conformation • 3rd in the region between alpha-helix and beta-sheet • 4th position prefer GLY, ASN, ASP CS 882 course project

10. Prediction of Turns [Chou 97’] • Site-independent model • based on knowledge that amino acid preferences at individual positions in ß-turns and does not consider any coupling between the residues in the sequence • 1-4 & 2-3 correlation model • based on residue coupling • Sequence coupled model • based on first-order markov chain involving conditional probabilities CS 882 course project

11. β–Hairpin Revisited [Gunasekaran 97’] • A data set of 250 non-homologous proteins • For 3 residue loops, major conformational motif is αR-αR-αL (type I followed by a residue in a left-handed helical conformation) • For 4 residue loops, αR-αR-αR-αL (π-turn motif) • Small polar residue ASN, ASP, SER, THR, GLY and PRO are preferred in loop • Identify several CYS-CYS pairs at the non-hydrogen bonded positions of beta stands CS 882 course project

12. β–Hairpin Folding Mechanism[Galzitskaya 02’] • Review experimental and theoretical studies of β–hairpin folding mechanism • Hydrogen-bond-centric model • Formation of folding droplet starting from beta turn is the determining factor • Hydrophobic-core-centric model • A core structure formed by side chains from both strands comes first, then brings the two strands together to form hydrogen bonds CS 882 course project

13. My Task Overview 1116 proteins resolution ≤ 1.6 A Non-homologous Extract beta hairpins Identify loop length Classify hairpins based on loop length Analysis residue preferences Cluster hairpins based on RMSD CS 882 course project

14. Distribution of β–Hairpins Based on Loop Length CS 882 course project

15. Amino Acids Distributions in Loop Regions • The number of a residue i over the total number of residues in loop regions CS 882 course project

16. A.A. with hydrophilic side A. A. that are in between CS 882 course project

17. Amino Acids Distributions in 2 Residues Loops • The number of a residue i occurs at position j over the total number of residues at position j. CS 882 course project

18. Amino Acid Distributions in 4 Residues Loops CS 882 course project

19. Position Preference of Amino Acids in 5 Residues Loops • A residue’s preference for a loop position • Fijis the number of times residue i occurs in a loop position j • Diis the number of times residue i occurs in the loop region CS 882 course project

20. Position Preference of Amino Acids in 5 Residues Loops CS 882 course project

21. Considering Structural Similarity • Further cluster beta hairpins based on structural similarity of loop region • Analysis the amino acid distributions in each cluster CS 882 course project

22. RMSD • Measure the structure similarity between two proteins • Given the position vectors of two sequences of amino acids V, W CS 882 course project

23. Candidate Clustering Algorithms • Partition methods • K-means / Quality Threshold • Hierarchical clustering method • UPGMA / Diana • Fuzzy logic based method • Fuzzy c-means clustering / Fanny • Neural network based methods • SOM / SOTA CS 882 course project

24. Reference • Sibanda BL, Thornton JM. Beta-hairpin families in globular proteins. Nature 1985. 316(6024):170–174. • Chou, K.C. and Blinn, J.R. Classification and prediction of beta-turn types. Protein Chem. 1997. 16, 575-595. • Gunasekaran K, Ramakrishnan C, Balaram P. Beta-hairpins in proteins revisited: lessons for de novo design. Protein Eng. 1997 Oct;10(10):1131-41. • Galzitskaya, O. V., J. Higo, and A. V. Finkelstein. 2002. Alpha-helix and beta-hairpin folding from experiment, analytical theory and molecular dynamics simulations. Curr. Protein Pept. Sci. 3:191–200. CS 882 course project

25. Thank you CS 882 course project