Xin Zhan CS 882 course project 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)

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

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’]

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

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

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

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

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

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

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

Xin Zhan CS 882 course project 13

My Task Overview

Extract beta hairpins

Identify loop lengthClassify hairpins based on loop length

Cluster hairpins based on RMSD

1116 proteinsresolution ≤ 1.6 ANon-homologous

Analysis residue preferences

Xin Zhan CS 882 course project 14

Distribution of β–Hairpins Based on Loop Length

53

896

336

520 498

296188 164

114 84

0100200300400500600700800900

1000

1 2 3 4 5 6 7 8 9 10

Loop length

Num

ber

of b

eta

hair

pins

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Amino Acids Distributions in Loop Regions The number of a residue i over the total

number of residues in loop regions

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

ALA ARG ASN ASP GLU GLY LYS PRO SER THR

2 residues loops 4 residues loops 5 residues loops

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A.A. with hydrophilic side A. A. that are in between

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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.

00.050.1

0.150.2

0.25

0.30.350.4

0.450.5

L1 L2

Rat

io o

f re

sidu

es ASNASPGLYLYSPROSER

Xin Zhan CS 882 course project 18

Amino Acid Distributions in 4 Residues Loops

0

0.05

0.1

0.15

0.2

0.25

L1 L2 L3 L4

Rat

io o

f re

sidu

es ASNASPGLUGLYPROSER

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

0

0.5

1

1.5

2

2.5

3

3.5

L1 L2 L3 L4 L5

Pre

fere

nce

ASNASPGLUGLYPROSERTHR

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Considering Structural Similarity

Further cluster beta hairpins based on structural similarity of loop region

Analysis the amino acid distributions in each cluster

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RMSD

Measure the structure similarity between two proteins

Given the position vectors of two sequences of amino acids V, W

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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

Xin Zhan 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.

Xin Zhan CS 882 course project 25

Thank you