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Lecture 47:
Structure II -- Proteins
Today’s Outline
• The monomers: amino acids
– Side chain characteristics
– Acid-base equilibria and pKa
• Peptide backbone
– Peptide bond formation
– Rotational degrees of freedom
– Common folding motifs
• Side chain interactions in folding
• (Time permitting) Levinthal’s paradox
This is not intended as
a Fischer projection!
First AA in
most proteins
Bulkiest
isoleucine
Isomers
Smallest
Covalent bond between
side chain and
These three are the
most commonly
phosphorylated
residues in eukaryotes
Umami flavor of
MSG
Neurotransmitter
As appropriate a time as any: pKa
As appropriate a time as any: pKa
Rearranging, we get:
When pH >> pKa,
[A-] >> [HA]
When pH << pKa,
[A-] << [HA]
When pH = pKa,
[A-] = [HA]
Strong acids have low pKas:
• HBr:
-10
• HCl:
-7
Weaker acids have low-ish pKas:
• H2PO4: 2
• HF:
3
• D/E:
4
Umami flavor of
MSG
Neurotransmitter
pKa = 3.9
pKa = 4.1
pKa = 10.5
pKa = 12.5
pKa = 6.0
Peptide bonds link amino acids
A protein’s folded shape can be roughly
described by the path traced by its
peptide backbone (ignoring sidechains)
Peptide bonds have limited
rotational freedom
The peptide bond
is planar:
The peptide bond has
two conformations
…but cis is less likely due
to steric clash
Most backbone rotation occurs via
phi (f) and psi (y) torsion angles
Some combinations of torsion angles
are much more likely than others
Ramachandran plot:
shows frequency of (f,y)
observed for residues in
folded proteins
Ball-and-stick models provide
some insight on infrequency of f >0
Glycine does adopt
positive f values
Less steric hindrance
because side chain (green) is
very small
Proline’s f value is (somewhat) fixed by
its side chain’s bond to the backbone
This side chain can clash
sterically with the preceding
amino acid, so the“preproline” Ramachandran plot
is also unique
Pre-proline Ramachandran plot
Another trend for consecutive amino
acids: correlation in position
Amino acid n
Amino acid n+1
What do we get
if we repeat the
same torsion
angles many
times in a row?
PyMOL interactive
PyMOL interactive
These amino acids
participate in the more
common, right-handed
form of helices
PyMOL interactive
Other right-handed helices
besides alpha helices have
similar torsion angles
a helix
310 helix
p helix
PyMOL interactive
PyMOL interactive
These amino acids are
part of beta sheets
PyMOL non-interactive
These amino acids
participate in the less
common, left-handed
forms of helices
Most of the residues in most
folded proteins participate in
one of these motifs
Peptide backbone hydrogen bonding is
the most common motif in folding
• The pattern of backbone hydrogen bonding is
referred to as a protein’s secondary structure
• Some side chains inhibit formation of certain
secondary structures (e.g. proline/a helices)
• With those exceptions, secondary structures
are not dependent on amino acid sequence
Does hydrogen bonding
in secondary structures
drive protein folding?
What interactions between side chains
drive sequence-specific protein folding?
Hydrophobic effect
Steric clash
What interactions between side chains
drive sequence-specific protein folding?
These forces determine the relative
orientation of a protein’s secondary
structures, i.e., the protein’s tertiary
structure
The same forces that drive tertiary
structure formation can also hold two
or more proteins together
Hydrophobic effect and vdW forces
drive leucine zipper folding
Covalent disulfide bonds can form
between cysteines
Reduction potentials:
Cysteines:
-222 mV
NADH:
-320 mV
Formal collaboration policy
This course encourages collaboration, which is a key to learning and the progress of
science. You may talk together about approaches to problems and you may work
together to perform calculations or write code. But any formal assignments that you are
given must be written, rather than copied, by you and you only, with the exception of
computer code, where the code may be written communally, but all code must be well
commented, and all comments in graded code must be written by you, on your own.
Since the goal of assignments is to help you and us assess your level of understanding of
the material, we require that you understand both the conceptual structure and the
details of each individual step of any answer you submit and we may ask you to answer
questions, orally, about an assignment, to demonstrate that you have achieved this level
of understanding.