Transcript Lect 9: BioMacromolecular Visualization I: Principles of

LSM2104/CZ2251
Essential Bioinformatics and Biocomputing
Protein Structure and
Visualization
Chen Yu Zong
[email protected]
6874-6877
LSM2104/CZ2251
Essential Bioinformatics and Biocomputing
Three Lectures
Lecture 9: BioMacromolecular Visualization I
Principles of protein chemistry and structure
Lecture 10: BioMacromolecular Visualization II
Protein structure databases; visualization;
and classifications
Lecture 11: Receptor Ligand Binding, Energy
Minimization and docking conceptsStructural Modeling
LSM2104/CZ2251
Essential Bioinformatics and Biocomputing
Lecture 9
Principles of Protein Chemistry and Structure
1. Why protein structure?
2. Structure organization
•Building blocks (amino acids), primary structure
•Secondary structure
•Super-secondary structure
•Tertiary structure
•Quaternary structure
•Multi-domain proteins
Why protein structure?
In the post-genomic era, focus has been extended
from sequence to structure
The advent of the post-genomic era
Mechanism of Protein function
Drug Receptors
Mad cows disease and the Prion protein
Prion protein------Memory?
Protein mis-folding can cause diseases
Mad cows disease and the Prion protein
Prion protein------Memory?
Protein mis-folding
can cause diseases
Drug Design: Success Story of Anti-HIV
HIV-1 protease
Specific disease proteins are targets for drug discovery
Knowledge of their structure useful for drug design
Protein sequence-structure-function relationship
Protein structure determines its function
Function of Proteins is determined
by their four level structures
Primary - Sequence of amino acids
Secondary - Shape of specific region
along chain mostly through Hbonding
Tertiary - 3 Dimensional structure of
globular protein through molecular
folding
Quaternary - Combination of separate
polypeptide and prosthetic group.
Aggregation and prosthetic.
1. Primary structure
Proteins are polymers of a set of 20 amino acids.
20 amino acids = building units.
Chiral Center
asymmetric carbon
The general formula for α-amino acid.
20 different R groups in the commonly occurring
amino acids.
All naturally occurring amino acids that
make up proteins are in the L conformation
The CORN method for L isomers: put the hydrogen
towards you and read off CO R N clockwise
around the Ca This works for all amino acids.
Classification of 20 R groups
Aliphatic residues
Aromatic residues
Acidic
Negatively charged
Charged residues
Basic
Positively charged
Neutral-Polar residues
The unique couple
Cg
Side chain = H
H
Ca
Cb
Imino
Cd
Ca
Structure of peptide bonds
Through hydrolysis reactions, amino acids are connected
through peptide bond to form a peptide/protein.
O
H 2N
CH
O
C
OH
H N
H
CH
CH3
C
OH
CH2
SH
O
H 2N
CH
CH3
O
C
N
H
CH
CH2
Amide
Ala Val
SH
C
OH
+ H2O
• Key features:
–
–
–
–
1. Planar
2. Rigid due to partial double bond character.
3. Almost always in trans configuration.
4. Polar. Can form at least two hydrogen bonds.
The peptide unit is a planar,
rigid structure
Peptide Unit
The peptide bond has a partial double-bonded character
due to delocalization of the electron pair of the C=O group.
Its bond length 1.33 Å is shorter than the C-N bond length
(1.45 Å), about 40% double bond character.
The peptide unit is a planar,
rigid structure
Each unit can rotate around two bonds (two degrees
of freedom):
Ca -C bond
angle of rotation psi ()
N- Ca bond
angle of rotation phi ()
Computed Ramachandran Plot
White = sterically
disallowed
conformations
(atoms come closer
than sum of van der
Waals radii)
Blue = sterically
allowed
conformations
Van der Waals Interactions
• van der Waals attraction
occurs at short range, and
rapidly dies off as the
interacting atoms move
apart.
• Repulsion occurs when the
distance between
interacting atoms becomes
even slightly less than the
sum of their contact
distance.
Van der Waals radii is the value of rij of the lowest van der
Waals energy
2. Secondary structure
Local organization mainly involving the
protein backbone:
-a-helix,
-b-strand (further assemble into b-sheets)
-turn and interconnecting loop
The (right-handed) a-helix
-d
i+8
i+4
Hydrogen
bond
i
+d
• First structure to be predicted
(Pauling, Corey, Branson:
1951) and experimentally
solved (Kendrew et al. 1958)
– myoglobin
• Turn: 3.6 residues
• Pitch: 5.4 Å/turn
• Rise: 1.5 Å/residue
Helix and Ramachandran Plot
The b-sheet
• Side chains project alternately up or down
b strand
b-Sheet and Ramachandran Plot
Turn Structures
Loop structures
Ramachandran plot and
Secondary Structure
3. Super secondary structure
& motif
Super secondary & motif: Secondary structures
organized in specific geometric arrangements.
4.1. b-hairpins: the most simple super
secondary structure
4.2. b-corners
4.3. Helix hairpins
Combination of basic
secondary structures
4.4. The a-a corner
4.5. Helix-turn-helix
4.6. b-a-b motifs
Details: http://www.expasy.org/swissmod/course/text/chapter2.htm
3.1. b-hairpins
3.2. b-corners
3.3. Helix hairpins
3.4. The a-a corner
3.5. Helix-turn-helix
3.6. b-a-b motifs
4. Tertiary structure
– secondary structure
elements pack into a
compact spatial unit
– “Two methods now
available to determine
3D structures of proteins:
X-ray crystallography
and Nuclear Magnetic
Resonance (NMR)
Secondary Structural Components of Protein
The three-dimensional structure of a
protein is determined by non-covalent
interactions among amino acids
•1. Hydrophobic region (nonpolar R- interactions)
R-CH3 --- H3C-R
•2. H-bonding between R-group G-OH --- N=R
•3. Salt bridge R-COO- --- +NH3-R
•4. van der Waals forces
Hydrophobic Interactions in Protein
Hydrogen Bond Interactions in Protein
The classic experiment by Anfinsen
in 1950s on Ribonuclease
Native state
catalytically active
addition of urea and
mercaptoethanol
Unfolded state;
inactive. Disulfide reduced
removal of urea and
mercaptoethanol
Native, catalytically
active state.
Disulfide correctly re-formed.
Disulfide Bridges

Disulfide bridges
in extracellular
proteins
 oxidation of 2
cysteine SH
groups
 Covalent S-S
bond formed.
Driving Forces in Folding
• Hydrophobic effect
– bury hydrophobic side chains
– expose polar/charged side chains to solvent
– ion-pair or “salt-bridge” for buried charges
• Hydrogen bonding
– between backbone N and O atoms
– between N, O and S side chain atoms
Side-chain
Interaction
•Amino acid sidechains interact
with each other
and irresponsible
for the globular
shape of the
protein.
5. Quaternary Structure
Highest level of protein organization
Referring to the arrangement of
homo- or heteromeric subunits (i.e.,
chains) and prosthetic groups i.e.,nonamino acid portion) fit as an
organized whole.
The quaternary structure of
deoxyhemoglobin
Hemoglobin - 4 chains:
2-a chain, 2-b chain
(Heme- four iron groups)
http://www.expasy.org/swissmod/course/text/chapter4.htm
Viral particles
Nano-structures
6. Multi-Domain Protein

Beads-on-a-string: sequential location:
tyrosine-protein kinase receptor TIE-1
(immunoglobulin, EGF, fibronectin type-3
and protein kinase); Grb4 adaptor protein

Domain insertions: “plugged-in” - pyruvate
kinase (1pkn)
a/b-1
All-b
a/b-1
a/b-2
Example of the Multi-domain Proteins
Beads-on-a-string
SH2
SH3
SH2
PH
C2
Domain insertions: “plugged-in”
pyruvate kinase
Summary

Why protein structure?

Protein structure organizations
Primary, secondary, tertiary,
quaternary structure,
viral particles,
multi-domain proteins