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Abbreviations and side chain polarity of

twenty amino acids

Basic side chains-positively charged at
physiological pH
Acid side chains-negatively charged
Polar side chains-interact well with water,
can form H-bonds
Nonpolar groups

Energetically unfavorable for them to contact water

Peptide bonds
• Covalent linkage between two amino acids
Peptide Bond
• A rigid, planar structure which is a consequence of resonance interactions
that give the peptide bond an 40% double-bond character

• The C—N bond is 0.13 Å shorter than its N—Cα single bond

• C==O bond is 0.02 Å longer than that of aldehydes and ketones.

Peptide bond

Trans Cis

Peptide groups, with few exceptions, assume the trans conformation: that in
which successive atoms are on opposite sides of the peptide bond joining them
The torsional degrees of freedom in a
peptide unit

• The only reasonably free movements are

rotations about the Cα—N bond and the
Cα—C bond.
• The torsion angles are both in the
conformation shown and increase, as
is indicated, in a clockwise manner when
viewed from .
Ramachandran Plot/ Diagram

• The sterically allowed values of ψ and φ can be determined by

calculating the distances between the atoms of a tripeptide at all
values of ψ and φ for the central peptide unit.

• Sterically forbidden conformations, are those in which any nonbonding

interatomic distance is less than its corresponding van der Waals

• Conformation map or Ramachandran diagram

The Ramachandran diagram

Blue - Regions of “normally allowed” ψ and φ angles

Green-shaded regions - Correspond to conformations having “outer

limit” van der Waals distances.
Conformation angles, ψ and φ of van der Waals Distances for
secondary structures Interatomic Contacts
Proteins are made up of a polypeptide backbone
with attached side chains
Characteristics of Polypeptide synthesis
• The amino group of one amino acid reacts with the carboxyl
group of another to form a peptide bond (=amide linkage) with
the elimination of a water molecule.

• The polarity of the molecule is retained. The monomers are all

joined together in the same orientation. The polypeptide chain
has polarity.

• The polypeptide contains a free amino group at one end and a

free carboxyl group at the other. These ends of the polypeptide
chain are referred to as the amino and carboxyl termini (ends)

• The product of the condensation reaction preserves the

reactive group (carboxyl group) at the end of the molecule. This
makes it possible for the peptide chain to join to yet another
amino acid.
Levels of organization of protein structure

• The primary structure of protein: a sequence of amino acids linked together

by peptide bonds (covalent bond)
• The secondary structure of protein: Polypeptide folding into α helix, β
sheet, or random coil (H bonds involved)
• The tertiary structure of protein: 3-D folding of a single polypeptide chain
(H bonds, disulfide bonds, ionic bonds, van der Waals interactions,
hydrophobic interactions)
• The quaternary structure of proteins: Association of two or more folded
polypeptides (sub units) to form a multimeric protein (bonds and
interactions similar to tertiary structure)
Primary structure (sequence of amino acids)
determines the structure of a protein
In water, hydrophobic aa cluster inside a folded
protein, away from solvent
Secondary structure of proteins
H bond between the N-H of every peptide bond to the C=O of the next
peptide bond of the same chain. R groups are not involved.
(e.g. in protein -keratin - abundant in skin, hair, nails and horns)

• The repeating unit is a single turn of the helix, which extends about 5.4 Å
along the long axis, slightly greater than the periodicity

• The amino acid residues in an α helix have conformations with ψ = -45° to

-50° and φ = -60°

• Each helical turn includes 3.6 amino acid residues.

• Helical pitch, p
• Number of repeating units per turn, n
• Helical rise per repeating unit, d
• Right- and left-handed helices are defined, respectively, as having
positive and negative values of n.

Right and left-handed helices Helical Dipole

Amino Acid Sequence Affects Helix Stability

 Interactions between amino acid side chains can stabilize or destabilize

this structure.
• If a polypeptide chain has a long block of Glu residues, this segment
of the chain will not form an helix at pH 7.0.
• Many adjacent Lys and/or Arg residues, which have positively
charged R groups at pH 7.0, will prevent formation of the helix.
• The bulk and shape of Asn, Ser, Thr, and Cys residues can also
destabilize an helix if they are close together in the chain.

 Positively charged amino acids are often found three residues away
from negatively charged amino acids, permitting the formation of an ion
 Two aromatic amino acid residues are often similarly spaced, resulting in
a hydrophobic interaction.
-helices can wrap around one another by interactions between their
hydrophobic side chains to form a stable coiled-coil.
e.g.  keratin in the skin and myosin in muscles
β sheet
• Polypeptide chains are held together by H bonds between N-H group of
one polypeptide chain and C=O group of the other chain
(e.g. in the protein fibroin - abundant in silk)
Beta Sheets
Beta Turns

• Beta turns that connect the ends of two adjacent segments of an

antiparallel beta sheet.
• The structure is a 180 turn involving four amino acid residues, with
the carbonyl oxygen of the first residue forming a hydrogen bond
with the amino-group hydrogen of the fourth.
Super-secondary structures
Tertiary structure of proteins

• 3D conformation or shape

• Depends on the properties of the R groups of amino

acid residues

• Fold spontaneously or with the help of molecular


• Stabilized by covalent and non-covalent bonds

Many proteins are composed of separate
functional domains

Protein domain: a segment (100 – 250 aa) of a polypeptide chain that

fold independently into a stable structure.
Forces stabilizing the tertiary structure of a
polypeptide chain

• Ionic bonds (usually between charged amino acid side chains at

cellular pH 7.0) (eg. Lys-NH3+ and Asp-COO-)
• Hydrogen bonds between R groups (remember uncharged polar
amino acids can H-bond!!! –Ser-OH, Thr-OH and Tyr-OH with
for example Glu=O or Gln=O)
• Covalent bonds (disulfide bonds between cysteines)
• Hydrophobic interactions-non-polar side chains associate in the
interior of the molecule and exclude water)
• van der Waals interactions
Noncovalent bonds help protein folding
Covalent disulfide bonds between adjacent cysteine side
chains help stabilize a favored protein conformation
Molecular chaperone proteins assist folding of
other proteins
Quaternary structure of proteins

Hemoglobin, a protein in red blood cells, has four sub units (two
copies each of - and β-globins containing a heme molecule
Gel electrophoresis method is used to separate proteins
Structural Bioinformatics Websites (URLs)
Structural Databases
Protein Data Bank (PDB):
Nucleic Acid Databank:
Molecular Modeling Database (MMDB):
PQS Protein Quaternary Structure Query Form at the EBI:
Molecular Graphics Programs/Plug-ins
Protein Explorer:
http://www.bernstein-plus-sons.com/software/rasmol/ and
Virtual Reality Modeling Language (VRML):
Requires a VRML plug-in, available
through http://www.web3d.org/vrml/vrml.htm
Structural Classification Algorithms
CATH (class, architecture, topology and homologous
CE (combinatorial extension of optimal pathway):
FSSP (fold classification based on structure–structure
alignment of proteins):
SCOP (structural classification of proteins):
VAST (vector alignment search tool):