Chem 501 Lecture 1

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Chemistry 501 Handout 4The Three-Dimensional
Structure of ProteinsChapter 4
Lehninger. Principles of Biochemistry. by Nelson
and Cox, 5th Edition W.H. Freeman and Company
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A proteins conformation is stabilized largely
by weak interactions
Proteins in any of their functional, folded
conformations are called native proteins.
Glycine

• Quaternary structure of deoxyhemoglobin
• (a) A ribbon representation
• (b) A space-filling model

Structure of the enzyme chymotrypsin, a globular
protein (PDB file 6GCH)
The known 3-D structures of proteins are archived
in the Protein Data Bank (PDB). Each structure is
assigned a four-character identifier, or PDB ID.
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Protein Architecture - Primary Structure
The planar peptide bond
Each peptide bond has some double bond character
due to resonance and cannot rotate
Series of rigid planes sharing a common point of
rotation at Ca
Three bonds separate the a carbons in a
polypeptide chain
? ? 180o when the peptide is in its fully
extended conformation and all peptide groups
are in the same plane
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Convention In this conformation, f y
0o In a protein, this conformation is prohibited
by steric overlap between an a-carbonyl oxygen
and an a-amino hydrogen atom
Ramachandran plot for L-Ala residues Conformation
s deemed possible are those that involve little
or no steric interference, based on calculations
using known van der Walls Radii and bond angles
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Protein Architecture - Secondary Structure
A few types of secondary structures are
particularly stable and occur widely in
proteins. Most prominent a helix and b
conformations.
Space-filling model
Note The a helix is not hollow
Ball-and-stick model
Ball-and-stick model of a right-handed a helix,
showing the intrachain H bonds
The a helix as viewed from one end, looking
down the longitudinal axis
The atoms in the center of the a helix are in
very close contact
Helical wheel representation of an a helix.
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Not all polypeptides can form a stable a helix.
Interactions between side chains can stabilize
of destabilize this structure
The identity of the amino acid residues near the
ends of the a-helical segment also affects the
stability of the helix
Arg103
Asp100
Interaction between R groups of amino acids
three residues apart in an a helix
Troponin C (shown a helix segment 13 residues
long)
The four amino acid residues at each end of the
helix do not participate fully in the helix
hydrogen bonds
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b turns are common in proteins
The b conformation organizes polypeptide chains
into sheets
180o turn involving four amino acid residues
Gly and Pro residues often occur in b turns Gly -
small and flexible Pro - the cis configuration is
particularly amenable to a tight turn
b sheets
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Common secondary structures have characteristic
bond angles and amino acid content
Ramachandran plots for a variety of structures
Common secondary structures can be assessed by
circular dichroism (CD) spectroscopy
Pyruvate kinase (all amino acid residues except
Gly)
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Protein tertiary and quaternary structures
a helix
loop
deoxyhemoglobin
b conformation
Tertiary structure includes long-range aspects
of amino acid sequence
Quaternary structure includes the
three-dimensional arrangement of polypeptide
chains in multisubunit proteins
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Example of quaternary structure
Fibrous Proteins (structure, support, shape,
protection) - Polypeptide chains arranged in long
strands of sheets
left-handed supertwisted coiled coil
Disulfide (-S-S-) bonds stabilize the
quarternary structure
Permanent waving
a-Keratin
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Collagen (connective tissue, tendons, cartilage,
organic matrix of bone, cornea)
Structure of collagen fibrils
The three-stranded collagen superhelix shown from
one end (ball-and-stick representation)
Three helix wrap around one another with a
right-handed twist

• chain repeating tripeptide sequence (generally
  Gly-X-Y, where X is often
• Pro and Y is often 4-Hyp)adopts a left-handed
  helical structure with three residues per turn

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Structure of silk
Fibroin layers of antiparallel b sheets rich in
Ala and Gly residues
Permits close packing and interlocking of R
groups
Sheets held together by numerous weak
interactions, rather than covalent bonds such as
disulfide bonds in a-keratin
Strands of fibroin (blue) emerge from the
spinnerets of a spider (colorized electron
micrograph)
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Globular Proteins Structures compact and varied
Tertiary structure of a small globular protein
sperm whale myoglobin
e.g. human serum albumin 585 residues in a single
chain (Mr 64,500)
Approximate dimensions its single polypeptide
chain would have if it occurred entirely in
a) Polypeptide backbone shown in a ribbon
representation b) Surface contour image useful
for visualizing pockets in the protein c) Ribbon
representation including side chains for the
hydrophobic residues Leu, Ile, Val, and Phe d)
Space-filling model with all amino acid side
chains
The heme group
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Supersecondary structures (motifs, or simply
folds)
Particularly stable arrangements of several
elements of secondary structure and the
connections between them.
Motifs
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Stable folding patterns in proteins
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Protein motifs are the basis for protein
structural classification
Constructing large motifs from smaller ones
The Structural Classification of Proteins (SCOP)
database. Protein structures divided into four
classes all a all b a/b (a and b segments
interspersed or alternate) ab (a and b regions
are somewhat segregated) Within each class tens
to hundreds of different folding arrangements,
built up form increasingly identifiable
structures.
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Protein quaternary structures range from simple
dimers to large complexes
Viral capsids
Quaternary structure of deoxyhemoglobin
a) The coat protein of poliovirus assemble into
an icosahedron 300 Angstrons in diameter
b) Tabaco mosaic virus rod-shaped virus 3,000
Angstrons long and 180 Angstrons in diameter
with helical symmetry
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Protein denaturation and folding
Loss of protein structure results in loss of
function
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The thermodynamics of protein folding depicted
as a free-energy funnel
Polypeptides fold rapidly by a stepwise process
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Folding for many proteins is facilitated by the
action of specialized proteins (chaperones)
E. Coli chaperone proteins DnaK and DnaJ
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Chaperonins in protein folding
GroEL/GroES complex
Proposed pathway for the action of the E. coli
chaperonins GroEL and GroES.
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Defects in protein folding may be the molecular
basis for a wide range of genetic disorders
Formation of disease-causing amyloid fibrils
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Prion Diseases
Stained section of cerebral cortex from autopsy
of a patient with Creutzfeldt-Jakob disease
shows spongiform (vacuolar) degeneration, the
most characteristic neurohistological feature.
Structure of the globular domain of human PrP in
monomeric (left) and dimeric (right) forms.
Proteinaceous infectious only protein (PrP)
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