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The Structure of Proteins

Head of Medusa Caravaggio, 1599

Proteins are polymers of Amino acids


Last day we considered the structure and chemical characteristics of amino acids.
Today we will examine how they polymerize together and form higher order structure.

H3N C C
O
H

The
zwitterionic form of
an amino acid

= the alpha () Carbon

Amino acid polymerization


the peptide bond forms via a condensation or dehydration reaction.

R1

H3N C C
O
H

R1

H H

H +
O
H NCC
O
H
H

H3N C C N C C
O
R2
H O
=

R2

the peptide bond

H2O

A more accurate depiction from your textbook:


it depicts the COO- charge as de-localized over the entire group

both the H atom and R groups are opposite of the carbonyl O atom to avoid steric
clash

The Primary (1o) Structure of Proteins


primary structure of protein refers to the sequence of amino acids in the protein, as
specified by the gene sequence encoding the protein

most proteins consist of between 50 to 2000 amino acids


the largest known protein is titin, a muscle protein consisting of 27,000 amino acids

amino acid polymers of less than 50 amino acids are often called peptides though
there is no strict cut off between the terms peptide and protein

the Carbon of each amino acid can always be recognized since the R group
is attached
the peptide bond occurs between the carbonyl group of the first amino acid and the
amine group of the next amino acid

Identify the Carbon and the Side chain (R group) of each amino acid in this
five amino acid peptide.
Locate each peptide bond in the peptide.

Note that every peptide or protein begins with the amino group of the first
amino acid and ends with the carboxyl group of the last amino acid.
Thus we refer to the start of a protein as the Amino terminus or N-terminus
and the end of a protein as the Carboxyl terminus or C-terminus

The Nature of the Peptide Bond


the structure of the amino acid chain about the peptide bond is planar and rigid
free to
rotate

Planar
Rigid

free to
rotate

Why the peptide bond is rigid


the peptide bond has a resonance structure shared with the carbonyl group
as with all resonance bonds, they are neither single or double bonds, but a
hybrid between the two. Since the peptide bond is not a pure single bond,
free rotation is not possible.

But, proteins have a very complex and convoluted structure and this is due to
the bonds that can rotate somewhat freely

free to
rotate

free to
rotate

Planar
Rigid

The bonds before and after the peptide bond can rotate
these are the bonds that flank the alpha Carbon of each amino acid
peptide bonds

(phi) bond rotation after peptide bond


(psi) bond rotation before peptide bond

peptide bonds

The phi and psi bonds have rotational freedom, but not unlimited freedom

Permissible
Not Permissible

=-180o, =+180o

=-0o, =+180o

=-180o, =+0o
Nelson p144

A Ramachandran Plot shows the permissible phi () and


psi () bond angles allowed in polypeptide backbone
beta strand

the range of permissible bond


angle combinations reflect
the secondary structures we
see in proteins
i.e. alpha helices and beta strands
alpha helix

The phi and psi bond angles


define the overall secondary and
tertiary structure of a protein
If we know the angle of every bond
in a protein, we know its exact structure

Nelson p103

The Secondary (2o) Structure of Proteins

the polypeptide chain can adopt several higher order structures

because of the permissible phi and psi bond angles within amino acids,
the polypeptide or protein backbone can form a (not unlimited) range of
conformations.

Hydrogen bonding between functional groups on the amino acids result


in the formation of regular structures (SECONDARY STRUCTURES) that help
determine the overall structure of the protein.

due to the combination of possible bond angles coupled with Hydrogen bonding
effects, certain amino acid segments spontaneously form secondary structures

secondary structures include the:


Alpha () Helix
Beta () Sheet
Turns and Loops

some proteins are made up of only -helices or only -sheets while others are
mixtures of both secondary structure types. Loops and turns often connect
helices or sheets together.

The Alpha Helix


alpha helices are segments of amino acids in proteins that form a helical structure
average length of 10 amino acids though may be shorter or longer
there are about 3.6 amino acids per turn of the helix
every fourth amino acid interacts via Hydrogen bonding
not all amino acids participate in alpha helix formation, the geometry or the
size of the side-chains of some amino acids make them unsuitable for
alpha helix formation

VDGQFEQKKKQKDETYDIEHLIACFSPMIRKKLSNTSYQEREDLEQELKIKMFEKADMLLCQDVPGFWEFILYMVDENS

N
Primary sequence and predicted secondary structure of a small 79 amino acid protein

Views of the Alpha Helix


Hydrogen bonding

Side-chains on outside of helix

H-bonding every 4 residues


Nelson p149

A protein composed of all alpha helices

The Beta Sheet


an important secondary structure in many proteins

blue =amino nitrogen


green = side chain
red = oxygen
black = carbon

composed of adjacent beta strands in anti-parallel or parallel arrangements


beta strands are segments of amino acids in a fully extended sequence rather
then coiled as in an alpha helix.

each amino acid binds


to opposite residue

each amino acid binds


to two opposite residues

Many Beta strands can associate in mixed orientations to form beta sheets
stabilized by intra-molecular H bonding

in all beta strands/sheets, note the orientation of the side chains

Beta sheets are usually depicted as flat arrows

Anti-parallel arrangement

Parallel arrangement

The arrangement of beta strands in some proteins

Turns and Loops


structured or unstructured segments of amino acids
often join other secondary structures together

Proline and Glycine often participate in forming turns (nearly 180o change in direction
of polypeptide backbone)
Proline at either one of
these positions will mediate
a Turn

Ala

Pro

proline forces a turn


in the backbone

Nothing (almost nothing) is random about protein structure.


Amino acid segments of the protein adopt specific secondary structures not by chance
but because of the characteristics of the amino acid participants

Tertiary Structure of Proteins


proteins may be very small or large (thousands of amino acids long)
amino acids form segments of secondary structure ( helices and sheets)

tertiary structure arises when these secondary structure segments associate in


specific and precise ways to form a 3-D compact structure
there is little or no open space within the interior of a protein
interior is usually hydrophobic and water is excluded from interior
forces that stabilize the tertiary structure

-charge interactions (e.g. between the + and - charged amino acids)


-H-bonding between polar groups
-van der Waals interactions between hydrophobic amino acid side chains
-the hydrophobic effect
-disulfide bonds between cysteine side-chains

Some Interactions that stabilize the tertiary structure


of Proteins

Charge-charge (ionic) Interactions


van der Waals Interactions

3. Induced dipole-induced dipole. Random


fluctuations in electron distribution in one
molecule sets up temporary dipole. This induces
dipole in adjacent molecule, resulting in
interaction. Weak but very important to the
cohesiveness of everything.
Also known as London Dispersion Forces.

Some Interactions that stabilize the tertiary structure


of Proteins
Disulfide bond formation

Disulfide bonds can be intra- or inter molecular

The Tertiary Structure of some proteins

Nelson p175

Proteins are not usually open structures

VDGQFEQKKKQKDETYDIEHLIACFSPMIRKKLSNTSYQEREDLEQELKIKMFEKADMLLCQDVPGFWEFILYMVDENS

C
Primary sequence and predicted secondary structure of a small 79 amino acid protein

Some Proteins fold into multiple tertiary structures called DOMAINS

each domain may possess a unique enzymatic function


that may be quite functional even if separated from the
rest of the protein

Discrete regions of a protein, or a domain in a protein, with special functional


significance are called MOTIFS.

The Helix-turn-Helix motif is


often found in proteins that
bind double-stranded DNA

The Quaternary Structure of Proteins


proteins fold into tertiary structures that are often active and do work
sometimes separate proteins interact with other proteins to form multi-subunit
proteins
sometimes proteins associate with themselves to form

homodimers
homotrimers
homotetramers
etc.

2 subunits or with other proteins (heterodimers)


3 subunits
4 subunits

sometimes very different proteins assemble into multi-subunit complexes


e.g. DNA polymerase required for DNA replication is made up of many
different proteins that interact with each other to form a
complex
-only together do they form an active enzyme
all the usual molecular interaction types are involved in these formations

Higher order assemblies of proteins (dimers, trimers, etc.)

Nelson p183

Quaternary structure of RNA polymerase

this is the enzyme that


synthesizes mRNA during
transcription - the first step
in gene expression.
it is made up of several different
proteins.

This Lecture
Stryer 8th Chapter 2 Protein Composition and Structure pg 27-57
Next Lecture
Stryer 8th Chapter 3 Exploring Proteins and Proteomes pg 66-79