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Biofundamentals - Peptide bonds and polypeptides
9/27/08 10:44 AM
Peptide bonds, polypeptides and proteins
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We have already mentioned proteins, since there are few biological processes that
do not rely on them.
Proteins derive their name from the ancient Greek sea-god Proteus who, like your
typical sea-god, could change shape. The name acknowledges the many different
properties and functions of proteins.
Proteins can act as catalysts and regulators of chemical reactions – we have already
seen how proteins act to regulate transport across membranes. Proteins control the
expression of genes, how genes respond to internal and external signals, and the
replication of the genetic material.
They can act as structural components, determining both the shape and mechanical
properties of cells and tissues. They can be motors, responsible for movements
within cells and the movement of cells, tissues and the organism as a whole.
Proteins are composed of α-amino acids linked
together by peptide bonds into polypeptide chains.
An amino acid is characterized by an amino group (NH 2 ) and a carboxylic acid group (-COOH) linked to a
carbon, known as the α-carbon.
Also attached to the αcarbon is a H and various
R-groups or "sidechains".
The four groups attached
to the α-carbon are
arranged at the vertices
of a tetrahedron.
If all four groups attached to
the α-carbon are different
from one another, as they
are in all amino acids except
glycine, the amino acid can
exist in two possible
stereoisomers, which are
known as enantiomers.
Enantiomers are mirror images of one another
and are termed the L- and D- forms.
Only L-type amino acids are found in proteins,
even though there is no obvious reason that
proteins could not have also been made using
both types of amino acids, or using D-amino
acids.
It is not that D-amino acids do not occur in nature, or in organisms, they do. They
are found in biomolecules, such as the antibiotic gramicidin, which is composed of
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Biofundamentals - Peptide bonds and polypeptides
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are found in biomolecules, such as the antibiotic gramicidin, which is composed of
alternating L-and D-type amino acids – however gramicidin is synthesized by a
different process than that used to synthesize proteins.
It appears that the universal use of L-type
amino acids is yet another example of the
evolutionary relatedness of organisms (it
appears to be a homologous trait).
Even though there are hundreds of
different amino acids known, only 19
amino acids and one imino acid, proline,
are found in proteins.
These amino acids differ in their R-groups.
Some of these R-groups are highly
hydrophobic, some are hydrophilic, some
are positively or negatively charged.
The different R-groups provide proteins
with a range of chemical properties.
In theory, what limits are there to the structure of an R-group?
Is the use of a common set of amino acids among living
organisms an analogous or a homologous trait?
Building a polypeptide: Polymers are chains of subunits, monomers, linked
together by chemical bonds.
The bond between two amino acids is known as a peptide bond. Two amino acids,
joined together by a peptide bond, is known as a dipeptide.
An amino acid polymer is known as a polypeptide. A polypeptide can be
composed of 20 different possible monomers that can, in theory, be linked together
in any imaginable order.
The formation of a peptide bond involves what is known as a condensation reaction.
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Biofundamentals - Peptide bonds and polypeptides
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In a condensation reaction two
molecules are joined together and
a molecule of water is released.
In a hydrolysis reaction, the
reverse occurs.
The addition of a water molecule is
associated with splitting the original
molecule into two.
In the case of both nucleic acids and polypeptides, polymer assembly involves a
condensation reaction (with the release of water), while polymer disassembly into
monomers involves a hydrolysis (with water as a reactant).
Polypeptides can be gives rise to very
large numbers of possible polypeptides;
there are 20100 different polypeptides that
are 100 amino acid residues long.
During the synthesis of a polypeptide, an
amino acid is attached to the C- or
carboxyl terminus of the existing chain.
This generates an unbranched, linear
polymer.
The peptide bond has a number of characteristics that are critical in determining how
polypeptides behave. Although drawn as a single bond, the peptide bond behaves
more like a double bond.
While there is free rotation around a
single bond, rotation around a peptide
bond is constrained.
Moreover, the carbonyl oxygen (C=O) acts as a H-bond acceptor, while
the amino hydrogen (-N-H) acts as a
H-bond donor.
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Proline is not an amino
acid, but rather an imino
acid.
Proline peptide bonds are found in the cis
configuration ~100 times as often as those between
other amino acids.
There is no H-bond donor in the proline peptide
bond and the presence of proline leads to a bend or
kink in the polypeptide chain.
Consider a condensation reaction; how would the reaction be
effected if we removed water from the system?
Are there any theoretical constraints on the order of monomers in
a polypeptide?
Why does it matter that rotation around a peptide bond is
"constrained"?
Water, polypeptide synthesis and folding: Were it not for the presence of
hydrophobic R-groups, all polypeptides would assume an extended configuration in
water. H-bond donors and acceptor groups in polypeptide backbone would form Hbonds with each other and with water molecules.
More typical polypeptides have all of the different R-groups in various proportions.
This sequence of amino acid residues, that is what is left of the amino acid once it is
part of the polypeptide, is known as the primary structure of the polypeptide.
We write the amino acid sequence of a polypeptide from its N- or amino terminus
to its C- or carboxyl terminus, with the N-terminus to the left and the C-terminus to
the right.
A number of the amino acid R-groups are hydrophobic. Their presence makes an
extended configuration for the polypeptide energetically unfavorable.
Very much like the process by which lipids self-assemble to form micelles and
bilayers, a typical polypeptide in aqueous solution will collapse onto itself in order to
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bilayers, a typical polypeptide in aqueous solution will collapse onto itself in order to
remove as many of these hydrophobic residues from contact with water as
possible.
It is a basic assumption of structural biology that the final folded state of a
polypeptide is determined by the sequence of amino acids along its length, and that
this final structure is the state of lowest, or close to the lowest, energy.
Protein structure is commonly presented in a
hierarchical manner.
While this is an over-simplification, it is a good place
to start.
As it is being synthesized, the process known as
translation, the polypeptide chain begins to fold. We
can think of the folding process as a walk across an
energy landscape.
The goal is to find the lowest point in the
landscape, the energy minimum of the system.
This is generally assumed to be the native or
functional state of the polypeptide.
The first step is the movement of hydrophobic
R-groups out of contact with water. This drives
the collapse of the polypeptide into a compact
and dynamic "molten globule".
The path to the native state is not necessarily a
smooth or predetermined one.
The folding polypeptide can get "stuck" in a local
energy minimum; there may not be enough energy
for it to get out again.
If a polypeptide gets stuck, there are mechanisms
to unfold it and let it try again to reach its native
state.This process of partial unfolding is carried out
by proteins known as chaperones.
What happens to a typical protein if you place it in a hydrophobic
solvent?
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Biofundamentals - Peptide bonds and polypeptides
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What would be the structure of a polypeptide if all of its R-groups
were hydrophilic?
What is the basic characteristic of the molten globule
configuration of a newly folded polypeptide?
How might a chaperone recognize a misfolded polypeptide?
Some amino acid R-groups contain carboxylic acid or amino groups, and so also act
as weak acids and bases.
Depending on the pH of the solution they
are in, these groups may be protonated
or unprotonated.
Whether a group is charged or uncharged
can have a dramatic effect on the
structure, and therefore the activity, of a
protein.
By regulating pH, an organism can
modulate the activity of specific proteins.
There are, in fact, compartments within
eukaryotic cells that are maintained at
low pH in part to regulate protein activity.
Why can changing the pH of the solution a protein finds itself in
alter the protein's structure.
Secondary structure features: All polypeptides share a common
backbone structure made up of peptide bonds. It is therefore not
surprising that there are common patterns in polypeptide folding.
The first of these, the α- heIix, was discovered by Linus Pauling and
Robert Corey, and reported in 1951. .
This was followed shortly thereafter by the structure of the β-sheet.
The forces that drive the formation of the α-helix and the β-sheet will
be familiar. They are they same forces that underlie water structure.
Linus at age 5
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In an α-helix and a β-sheet, all of the
possible H-bonds involving the peptide
bond's donor and acceptor groups are
formed.
This stabilizes the structure.
In an α-helix , the R-groups point
outward from the long axis of the helix.
In β-sheets, the Hbonds between the
peptide bond donor
and acceptor groups
are made between
either parallel or antiparallel polypeptide
chains.
These are anti-parallel ßsheets
The R-groups point out
of and into the plane of
the sheet.
The key factor that determines the specific details of polypeptide folding is the
interaction between R-groups, not only with one another but with water and
dissolved ions.
In a water soluble polypeptide, most but not necessarily all of the surface R-groups
will be hydrophilic. Hydrophobic groups will tend to be buried in the polypeptide's
interior.
Some polypeptides are inserted into membranes. In these polypeptides,
hydrophobic R-groups on the surface of the folded polypeptide will interact with the
hydrophobic interior of the lipid bilayer.
Other factors in protein structure: In addition to hydrophobic/hydrophilic effects,
ionic interactions between acidic and basic R-groups, van der Waals interactions
and H-bonds play an important role in determining the tertiary or three dimensional
structure of the polypeptide.
Proteins can include non-amino acid-based components, known generically as cofactors. A protein minus its cofactors is known as the apoprotein. Together with its
cofactors, it is known as the holoprotein. Generally, without its cofactors, a protein
is inactive and often unstable.
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Cofactors can range in complexity from a single metal atom to quite complex
molecules, such as vitamin B12 . For example, the retinal group of
bacteriorhodopsin is a co-factor.
A protein is a functional entity. In many cases a protein is
composed of multiple polypeptides.
A protein that contains multiple polypeptides, whether of the same
or different types, is said to have a quaternary structure.
A protein with two polypeptide subunits.
There are also higher levels of polypeptide organization. For
example, a specific polypeptide may be a component of a number
of different proteins.
Summarize the differences in structure between a protein that is
soluble in the cytoplasm and one that is buried in the membrane.
Why might proteins that require co-factors misfold in the absence
of the co-factor?
Any ideas about why cofactors might be necessary?
How could surface hydrophobic amino acid R-groups facilitate
protein-protein interactions.
Use Wikipedia | revised 27-Sep-2008
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