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M1 - Biochemistry
Protein Structure
Dr. Grogan
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NTPs
amino
acids
Structure
DNA
RNA
PROTEINS
Function
THE CENTRAL DOGMA
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Proteins are the principal
agents for expression of the
information contained in
the genome.
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Proteins have wide ranging
properties appropriate to
their various functions.
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Proteins may
differ greatly in
amino acid
composition.
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What can the amino acid
composition of a protein tell you
about its properties/function?
For example:
1. A protein that is rich in hydrophobic
amino acids
2. Histones – rich in Arg, Lys
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Proteins often have
constituents other than
amino acids.
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Proteins are constructed
from various combinations
of a relatively limited
number of structural
motifs.
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The Four Levels of Protein
Structure
• Primary – the covalent bonded amino acid
sequence
• Secondary – non-covalent interactions between
residues close to each other in the primary
sequence
• Tertiary – non-covalent or covalent interactions
between secondary structural elements
• Quaternary – non-covalent or covalent interactions
between different polypeptide chains
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The Four Levels of Protein Structure
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Even the simplest proteins
can assume many different
conformations.
BUT
Only one or a few of these
will be functional.
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The Concept of
Protein Folding
How does a protein assume
the conformation that will
permit it to carry out its
function?
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Unfolded
(denatured)
Folded
(native conformation)
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General Principles
Governing Protein Folding
• Dictated by initial primary
amino acid sequence
• Sequential formation of higher
order structures
• Minimal energy structure
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Characteristics of a Properly
Folded (minimal energy) Protein
• Hydrophobic residues in hydrophobic
core
• Most ionic and polar groups on surface
• Polar groups that are inside interact
with each other
• No overlap in van der Waal’s radii.
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Formation of Secondary Structure
• The most stable and common forms are αhelix and β-sheet structures
• Maximize hydrogen bonds between αaminos and α-carbonyls of peptide bonds
• Maximize electrostatic interactions between
R-groups
• Minimize steric clashes between R-groups
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How does amino acid
sequence determine
secondary structure?
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Recall: Double bond character
prevents rotation around the
peptide bond.
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The single bonds between the αcarbons and carbon and nitrogen of the
peptide bond remain free to rotate.
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However, steric hindrance limits that
rotation to a certain range of angles φ
and ψ.
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Steric Hindrance
Between an
Amino Hydrogen
and a Carbonyl
Oxygen with
Unfavorable
Angles φ and ψ
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β-sheet structures
α-helical structures
A Ramachandran plot showing angles
φ and ψ that avoid steric clashes.
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The α-helix
maximizes the
formation of Hbonds between the
α-amino hydrogen
and the carbonyl 4
residues removed
in the primary
sequence.
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Arg
Asp
The stabilizing effect on
the α-helix of
electrostatic interaction
between acidic and
basic amino acids, 3
residues apart.
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Conversely, bulky R-groups
located in close proximity
tend to destabilize an α-Helix
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Charge distribution on
the α-helix induces a
partial positive charge
at the amino terminus
and a partial negative
charge at the carboxyl
terminus.
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Effects of the Helical Dipole on
Stability
Acidic residues near the amino terminus stabilize.
Basic residues near the amino terminus destabilize.
Basic residues near the carboxyl terminus stabilize.
Acidic residues near the carboxl terminus destabilize.
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For reasons that we will discuss
later, Gly and Pro residues also
destabilize the α-helix.
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β-Sheet: Another Type of
Secondary Structure that
Maximizes Hydrogen Bonding
While Avoiding Steric Clashes
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Loops and Turns
Where the Polypeptide
Chain Becomes More
Disordered and Changes
Direction
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Gly and/or Pro residues disrupt
helical or sheet structures and
facilitate turns.
• Gly contributes necessary flexibility
because it lacks a bulky R-group.
• Pro lacks the flexibility to accommodate
helical or sheet structures but can form a cis
peptide bond to effect a 180 degree turn.
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For example, this sequence marks
the carboxyl terminus of an αhelix found in a family of
esterases:
Ala-Arg-Asn-Gly-Ser-Pro
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