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

2. Outline Research background about β-hairpin motif My task overview
Preliminary results
Future works
Xin Zhan
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 beta sheet
a special case of a turn
direction of protein backbone reverses
flanking secondary structure elements interact (hydrogen bonds)
Xin Zhan
CS 882 course project

4. Types of Turns β-turn (most common) δ-turn γ-turn α-turn π-turn ω-loop
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
Is characterized by…
1 Delta ; 2 gamma
People have found beta and pi turn occurring in beta hairpin
Xin Zhan
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’]
People have found..
The authors also classify hairpins based on loop length and conformations of loop regions.
Xin Zhan
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
Type 1, residue 2: as the required phi and psi angles are well outside the allowed regions of the Ramachandran plot for amino acids with side chains.
Type 1, residue 1: has a conformation which can only be adopted by glycine.
This is because amino acids other than glycine would cause steric hindrance involving the residue's side chain and the main chain.
Xin Zhan
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
Type 1, residue 2: as the required phi and psi angles are well outside the allowed regions of the Ramachandran plot for amino acids with side chains.
Type 1, residue 1: has a conformation which can only be adopted by glycine.
This is because amino acids other than glycine would cause steric hindrance involving the residue's side chain and the main chain.
Xin Zhan
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
3rd: as this adopts phi and psi angles close to the left-handed helical conformation
Xin Zhan
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
3rd: as this adopts phi and psi angles close to the left-handed helical conformation
Xin Zhan
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
The existing prediction methods can be classified into 3 categories
1 model is based on knowledge that..
2 model predict the ß-turns in proteins based on residue coupling. the coupling effect between the 1st and the 4th residues and that between the 2nd and the 3rd residues was given a special consideration.
Xin Zhan
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
Gave an reexamination of beta hairpin conformation.
Xin Zhan
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
The hydrogen-bond-centric model assumes that the formation of a folding droplet starting from the ß-turn is the determining factor in transition kinetics.
The hydrophobic-core-centric model proposes that a core structure formed by side chains from both strands comes first, and then brings the two strands together to form hydrogen bonds.
Xin Zhan
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
List is from PISCES, generated on Nov 11, 2006
Check secondary structures
Select anti-parallel beta strands
Verify no alpha helix between the strands
Analysis residue preferences
Cluster hairpins based on RMSD
Xin Zhan
CS 882 course project

14. Distribution of β–Hairpins Based on Loop Length
Top 3 are 2 4 and 5 residues loops. Next I get a close look at them.
Xin Zhan
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
Only shows the top 10, the last 8 always has the highest ratio
Charged Amino Acids: LYS GLU
Hydrophobic amino acids: ALA
Xin Zhan
CS 882 course project

16. A.A. with hydrophilic side A. A. that are in between
Xin Zhan
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.
GLY is favored , High beta turn propensity of GLY
Xin Zhan
CS 882 course project

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

19. Position Preference of Amino Acids in 5 Residues Loops
A residue’s preference for a loop position
Fij is the number of times residue i occurs in a loop position j
Di is the number of times residue i occurs in the loop region
Xin Zhan
CS 882 course project

20. Position Preference of Amino Acids in 5 Residues Loops
Xin Zhan
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
That ‘s all the experimental result I will show today.
Xin Zhan
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
Xin Zhan
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
SOM (self-organizing maps) and SOTA (self-organizing tree algorithm)
Xin Zhan
CS 882 course project

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

25. Thank you
Xin Zhan
CS 882 course project