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Protein Structure: protein
architectures
Park, Jong Hwa
MRC-DUNN
Hills Road Cambridge
CB2 2XY
England
Bioinformatics in Biosophy
:
Next
02/06/2001
Protein Shapes
In 1947, Max Perutz, MRC Laboratory of Molecular
Biology in Cambridge  Protein structure modelling
(or determination) using X-ray diffraction.
In 1950’s and 60’s, John Kendrew and Perutz solved the
structures of Myoglobin and Haemoglobin.
Since then many protein structures were solved in
Cambridge and the researchers who were trained in
Cambridge (many of them were americans).
Kendrew and Perutz found out that :
Structures are much more conserved than protein
sequences in terms of residue variability.
Modern Molecular biology has been dominated by
Structures.
It is because Structures are the most definite
representation of proteins.
http://www.techfak.uni-bielefeld.de/bcd/Curric/syllabi.html
What makes protein architecture
Protein structures need to achieve :
1) relatively Low energy conformation of individual residues(side
groups)
2) hydrogen bonding by polar groups, including buried ones
3) formation of compact, well-packed structures (for most of them).
For 1: Secondary structures are formed
For 2: Secondary structures are formed
For 3: Coils (turns) are used.
The study of protein architecture is largely a description
of the spatial assembly of helices and strands of sheet
within the structure.
Aminio Acid
Side chains (R):
The side chains confer important properties on a protein such as the ability
to bind ligands and catalyse biochemical reactions. They also direct the
folding of the nascent polypeptide and stabilise its final conformation.
Certain colours are used conventionally to represent the different atom types
found in proteins.
red is used for oxygen, blue for nitrogen, white for carbon and yellow for
sulphur.
Hydrogen atoms cannot be located in most protein structures since they
scatter X-rays too weakly.
Alipatic amino acid side groups and proline, glycine
Side Chain Carbon
The side chain atoms of amino acids are
named in the Greek alphabet according to
this scheme.
Side Chain Torsion Angle
The side chain torsion angles are named chi1,
chi2, chi3, etc., as shown below for lysine.
Chi 1 Angle restriction
The chi1 angle is subject to certain restrictions which arise
from steric hindrance between the gamma side chain
atom(s) and the main chain. The different conformations
of the side chain as a function of chi1 are refered to as
gauche(+), trans and gauche(-). These are indicated in
the diagrams below in which the amino acid is viewed
along the Cbeta-Calpha bond.
Gauche - : looking top-down
Trans form of Chi angle to C-alpha
Gauche + is dominent
• The most abundant conformation is gauche(+) in which the
gamma side chain atom is opposite to the residue's main chain
carbonyl group when viewed along the Cbeta-Calpha bond.
• The second most abundant conformation is trans in which the side
chain gamma atom is opposite the main chain nitrogen.
• The least abundant conformation is gauche(-) which occurs when
the side chain is opposite the hydrogen substituent on the Calpha
atom. This conformation is unstable because the gamma atom is in
close contact with the main chain CO and NH groups. The
gauche(-) conformation is occasionally adopted by serine or
threonine residues in a helix where the steric hindrance is offset by
a hydrogen bond between the gamma oxygen atom and the main
chain.
• With most amino acids the gauche(+) and trans conformations are
adopted with similar abundances although the gauche(+)
conformation tends to dominate.
Alpha Helix: N-H group in ith residue forms a
hydrogen bond to the O=C group of residue i+4
Almost of all alpha helix is right handed.
One residue to the next is about 100 degree
3D translation of 1.5 Angstrom in proteins.
3-10 helix: ith residue’s NH  O=C of
i+3th residue.
Pi-helix  ith => i+5th residue.
Where the stability is from 
Toilet roll representation of alpha
Distortions of alpha
The majority of alpha-helices in globular proteins are
curved or distorted somewhat compared with the
standard Pauling-Corey model.
These distortions arise from several factors including:
1. The packing of buried helices against other
secondary structure elements in the core of the
protein.
Distortions
1.
2.
3.
4.
5.
Proline residues induce distortions of around 20 degrees in the direction
of the helix axis. This is because proline cannot form a regular alphahelix due to steric hindrance arising from its cyclic side chain,
which also blocks the main chain N atom and chemically prevents it
forming a hydrogen bond.
Janet Thornton has shown that proline causes two H-bonds in the helix
to be broken since the NH group of the following residue is also
prevented from forming a good hydrogen bond. Helices containing
proline are usually long perhaps because shorter helices would be
destabilised by the presence of a proline residue too much.
Proline occurs more commonly in extended regions of polypeptide.
Solvent: Exposed helices are often bent away from the solvent region.
This is because the exposed C=O groups tend to point towards solvent to
maximise their H-bonding capacity, ie tend to form H-bonds to solvent
as well as N-H groups. This gives rise to a bend in the helix axis.
Solvent caused distortion of alpha
http://pps98.man.poznan.pl/ppscore/section3/jonc/helix2.html
3-10 helices
1. 310-Helices. Strictly, these form a distinct class of helix
2.
3.
but they are always short and frequently occur at the
termini of regular alpha-helices. The name 310 arises
because there are three residues per turn and ten atoms
enclosed in a ring formed by each hydrogen bond (note
the hydrogen atom is included in this count).
There are main chain hydrogen bonds between residues
separated by three residues along the chain (ie O(i) to
N(i+3)). In this nomenclature the Pauling-Corey alphahelix is a 3.6(13)-helix.
The dipoles of the 310-helix are not so well aligned as in
the alpha-helix, ie it is a less stable structure and side
chain packing is less favourable.
The a-helix conformation has a particular stability for
two main reasons.
1) Firstly the side chain groups are quite well
separated.
2) Secondly, and most importantly, each peptide link
is involved in two hydrogen bonds. (NH=> OC)
The atoms involved are arranged linearly (figure 8) so
that the hydrogen bonds are nearly at their
maximum strength. The hydrogen bonds run
down the length of the a-helix tube and lock the
conformation in place.
Alpha helix
The structure repeats itself every 5.4
Angstroms along the helix axis, ie we say
that the alpha-helix has a pitch of 5.4
Angstroms.
Alpha-helices have 3.6 amino acid residues
per turn, ie a helix 36 amino acids long
would form 10 turns.
Beta sheet: Parallel and anti-parallel
Beta Topology
Antiparallel beta-sheet
Beta sheets are twisted
Ramachandran plot
In a polypeptide the main chain N-C.alpha and C.alpha-C bonds
relatively are free to rotate. These rotations are represented by
the torsion angles phi and psi, respectively.
G N Ramachandran used computer models of small polypeptides
to systematically vary phi and psi with the objective of finding
stable conformations. For each conformation, the structure was
examined for close contacts between atoms.
Atoms were treated as hard spheres with dimensions
corresponding to their van der Waals radii.
Therefore, phi and psi angles which cause spheres to collide
correspond to sterically disallowed conformations of the
polypeptide backbone.
Ramachandran Plot pic.
Beta Bulge
One important distortion of the pleated beta-sheet is
known as the beta-bulge.
These distortions arise whenever an amino acid is
introduced in a beta-strand between residues which
are forming the closely spaced hydrogen bonding
pattern characteristic of beta-sheet. This disrupts the
sheet which means that beta-bulges can only occur in
an outer strand of the sheet. There are two main
classes of beta-bulge known as as the classic and the
G1 bulge.
BetaBulge in Ramachandran plot
BetaBulge
a classic beta-bulge at position
156 of the superoxide
dismutase from the
tuberculosis mycobacterium.
The rightmost of the three
strands contains the bulge and
the disruption to the sheet's
hydrogen bonding pattern can
be seen (dashed lines show Hbonds).
Reverse Turns
The structural elements that allow a sharp change of direction of
the polypeptide chain are called reverse turns.
Reverse turns are very abundant in globular proteins and generally
occur at the surface of the molecule.
It has been suggested that turn regions act as nucleation centres
during protein folding.
Reverse turns are divided into classes based on the type of
secondary structure they link, on the number of residues in the
turn and their phi and psi angles.
The nomenclature can be confusing in that the term reverse turn
and the terms for its subtypes are sometimes used
interchangeably. Further confusion may arise from differing
definitions.
 Gamma turns
Reverse Turns
Gammaturns include 3 consecutive residues and have a
hydrogen bond from the main chain carbonyl oxygen
O(i) to the main chain NH(i+2) group. Two types are
distinguished.
Betaturns include 4 consecutive residues and have a
distance of less than 7Å between the C -atoms of
residues i and i+3. Classically there is a hydrogen bond
present between the main chain carbonyl oxygen O(i)
and the main chain NH(i+3) group. Nine classes of
Betaturn can be distinguished.
Gamma Turn
Beta Turns (type 1 and 2)
Betaturns are divided into classes based on
the phi and psi angles of the residues at
positions i+1 and i+2. Types I and II shown
in the figure below are the most common
reverse turns, the essential difference
between them being the orientation of the
peptide bond between residues at (i+1) and
(i+2).
Type 1 and 2 , Beta Turns
The torsion angles for the residues (i+1) and (i+2) in the two types of turn lie in
distinct regions of the Ramachandran plot.
Disulphide Bond
Disulphide Bond
Disulphide bonds or bridges are covalent
bonds (ca. 2.08Å) and as such are part of the
primary structure of the protein. However,
they will also be involved in proper folding in
three dimensions because they may link up
non-consecutive parts of the polypeptide or
two individual polypeptides. The geometry of
disulphides can be described with 5 dihedral
angles.
Types of DS bond
A thiol group which may form a covalent link with the thiol
group of another cysteine.
Disulphide bridges are sensitive to reducing agents which convert
the two sulphur atoms back to their original
-S-H form.
Disulphide bridges are normally only present in extracellular
proteins.
References
•Introduction to Protein Structure, Branden, C. and Tooze, J. (1991)
Garland Publishing, New York
•Proteins, Creighton, T.E. (1993) 2nd edition, W.H. Freeman & Co.,
New York
•Principles of Protein Structure, Schulz, G.E. and Schirmer, R.H.
(1979) Springer-Verlag, New York
•Protein Structure - New Approaches to Disease and Therapy,
Perutz, M. (1992) W.H. Freeman & Co., New York
•Enzyme Structure and Mechanism, Fersht, A.R. (1976) 2nd ed., pub.
W.H.Freeman & Co., New York
•http://www.dcc.unicamp.br/~bio/ICMB.html