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Proteins: Their Structure and Biological Functions. Biological Functions of Proteins. Proteins are the agents of biological function Enzymes - Ribonuclease Regulatory proteins - Insulin, PCNA Transport proteins - Hemoglobin Structural proteins - Collagen

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Biological Functions of Proteins

Proteins are the agents of biological function

  • Enzymes - Ribonuclease
  • Regulatory proteins - Insulin, PCNA
  • Transport proteins - Hemoglobin
  • Structural proteins - Collagen
  • Contractile proteins - Actin, Myosin
  • Protective proteins - Antifreeze proteins

Protein structure often provides clues about protein function

Unrelated proteins assume similar structures to fulfill common functions

  • Short polymers of amino acids
  • Each unit is called a residue
  • 2 residues - dipeptide
  • 3 residues -tripeptide
  • 12-20 residues - oligopeptide
  • many - polypeptide

One or more polypeptide chains

  • One polypeptide chain - a monomeric protein
  • More than one - multimeric protein
  • Homomultimer - one kind of chain
  • Heteromultimer - two or more different chains
  • Hemoglobin, for example, is a heterotetramer;

it has two alpha chains and two beta chains

proteins large and small
Proteins - Large and Small
  • Insulin - A chain of 21 residues, B chain of 30 residues -total mol. wt. of 5,733
  • Glutamine synthetase - 12 subunits of 468 residues each - total mol. wt. of 600,000
  • Connectin proteins - alpha - MW 2.8 million!
  • beta connectin - MW of 2.1 million, with a length of 1000 nm -it can stretch to 3000 nm!

The Sequence of Amino Acids in a Protein

  • is a unique characteristic of every protein
  • is encoded by the nucleotide sequence of DNA
  • is thus a form of genetic information
  • is read from the amino terminus to the carboxyl terminus
The levels of protein structure

- Primary sequence

- Secondary local structures

- Tertiary overall 3-dimensional


- Quaternary subunit organization

what forces determine the structure
What forces determine the structure?
  • Primary structure - determined by covalent bonds
  • Secondary, Tertiary, Quaternary structures - all determined by weak forces

The Role of the Sequence in Protein Structure

All of the information necessary for folding the peptide chain into its "native” structure is contained in the primary amino acid structure of the peptide.

sequence determination
Sequence Determination

Frederick Sanger was the first - in 1953, he sequenced the two chains of insulin.

  • Sanger's results established that all of the molecules of a given protein have the same sequence
  • Proteins can be sequenced in two ways:

- real amino acid sequencing

- sequencing the corresponding DNA in the gene

nature of protein sequences
Nature of Protein Sequences
  • Sequences and composition reflect the function of the protein:
  • Membrane proteins have stretches of hydrophobic residues, whereas fibrous proteins may have atypical sequences
  • Homologous proteins from different organisms have similar sequences e.g., cytochrome c is highly conserved
phylogeny of cytochrome c
Phylogeny of Cytochrome c
  • The number of amino acid differences between two cytochrome c sequences is proportional to the phylogenetic difference between the species from which they are derived
  • This observation can be used to build phylogenetic trees of proteins
  • This is the basis for studies of molecular evolution

The Coplanar Nature of the Peptide Bond

Six atoms of the peptide group lie in a plane


The Peptide Bond

  • is usually found in the trans conformation
  • has partial (40%) double bond character
  • is about 0.133 nm long - shorter than a typical single bond but longer than a double bond
  • Due to the double bond character, the six atoms of the peptide bond group are always planar.
  • N partially positive; O partially negative
secondary structure
Secondary Structure

The atoms of the peptide bond lie in a plane

  • The resonance stabilization energy of the planar structure is 88 kJ/mol
  • A twist about the C-N bond involves a twist energy of 88 kJ/mol times the square of the twist angle.
  • Twists can occur about either of the bonds linking the alpha carbon to the other atoms of the peptide backbone
consequences of the amide plane
Consequences of the Amide Plane

Two degrees of freedom per residue for the peptide chain

  • Angle about the C(alpha)-N bond is denoted phi
  • Angle about the C(alpha)-C bond is denoted psi
  • The entire path of the peptide backbone is known if all phi and psi angles are specified
  • Some values of phi and psi are more likely than others.
steric constraints on phi psi
Steric Constraints on phi & psi

Unfavorable overlap precludes some combinations of phi and psi

  • phi = 0, psi = 180 is unfavorable
  • phi = 180, psi = 0 is unfavorable
  • phi = 0, psi = 0 is unfavorable
classes of secondary structure
Classes of Secondary Structure

All these are local structures that are stabilized by hydrogen bonds

  • Alpha helix
  • Beta sheet (composed of "beta strands")
  • Tight turns (aka beta turns or beta bends)
the alpha helix
The Alpha Helix
  • First proposed by Linus Pauling and Robert Corey in 1951
  • A ubiquitous component of proteins
  • Stabilized by H-bonds
the alpha helix36
The Alpha Helix
  • Residues per turn: 3.6
  • Rise per residue: 1.5 Angstroms
  • Rise per turn (pitch): 3.6 x 1.5A = 5.4 Angstroms
  • The backbone loop that is closed by any H-bond in an alpha helix contains 13 atoms
  • phi = -60 degrees, psi = -45 degrees
the beta pleated sheet
The Beta-Pleated Sheet

Composed of beta strands

  • Also first postulated by Pauling and Corey, 1951
  • Strands may be parallel or antiparallel
the beta turn
The Beta Turn

(aka beta bend, tight turn)

  • allows the peptide chain to reverse direction
  • carbonyl C of one residue is H-bonded to the amide proton of a residue three residues away
  • proline and glycine are prevalent in beta turns

Steric Constraints on phi & psi

  • G. N. Ramachandran was the first to demonstrate the convenience of plotting phi,psi combinations from known protein structures
  • The sterically favorable combinations are the basis for preferred secondary structures
predictive algorithms
Predictive Algorithms

If the sequence holds the secrets of folding, can we figure it out?

tertiary structure several important principles
Tertiary StructureSeveral important principles:
  • The backbone links between elements of secondary structure are usually short and direct
  • Proteins fold to make the most stable structures (make H-bonds and minimize solvent contact

Tertiary Structure

So, how do proteins fold?


Weak Forces are Responsible for Protein Folding

What are they?

What are the relevant numbers?

  • van der Waals: 0.4 - 4 kJ/mol
  • hydrogen bonds: 12-30 kJ/mol
  • ionic bonds: 20 kJ/mol
  • hydrophobic interactions: <40 kJ/mol
thermodynamics of folding
Thermodynamics of Folding
  • Separate the enthalpy and entropy terms for the peptide chain and the solvent

The largest favorable contribution to folding isthe entropy term

for the interaction of nonpolar residues with the solvent

tertiary structure several important principles53
Tertiary StructureSeveral important principles:
  • Secondary structures form wherever possible (due to formation of large numbers of H-bonds)
  • Helices and sheets often pack close together

How do proteins recognize and interpret the folding information?

  • Certain loci along the chain may act as nucleation points
  • Protein chain must avoid local energy minima
  • Chaperones may help
  • Peptide chains, composed of L-amino acids, have a tendency to undergo a "right-handed twist"

Globular Proteins

Some design principles

  • Most polar residues face the outside of the protein and interact with solvent
  • Most hydrophobic residues face the interior of the protein and interact with each other
  • Packing of residues is close
  • However, ratio of vdw volume to total volume is only 0.72 to 0.77, so empty space exists
  • The empty space is in the form of small cavities

Globular Proteins

The Forces That Drive Folding

  • Peptide chain must satisfy the constraints inherent in its own structure
  • Peptide chain must fold so as to "bury" the hydrophobic side chains, minimizing their contact with water

Globular Proteins

More design principles

  • "Random coil" is not random
  • Structures of globular proteins are not static
  • Various elements of protein move to different degrees
  • Some segments of proteins are very flexible and disordered

An amphiphilic helix in flavodoxin:

A nonpolar helix in citrate synthase:

A polar helix in calmodulin:

protein modules
Protein Modules

An important insight into protein structure

  • Many proteins are constructed as a composite of two or more "modules" or domains
  • Each of these is a recognizable domain that can also be found in other proteins
  • Sometimes modules are used repeatedly in the same protein
  • There is a genetic basis for the use of modules in nature
molecular chaperones
Molecular Chaperones
  • Why are chaperones needed if the information for folding is inherent in the sequence?
    • to protect nascent proteins from the concentrated protein matrix in the cell and perhaps to accelerate slow steps
  • Chaperone proteins were first identified as "heat-shock proteins" (hsp60 and hsp70)
other chemical groups in proteins
Other Chemical Groups in Proteins

Proteins may be "conjugated" with other chemical groups

  • If the non-amino acid part of the protein is important to its function, it is called a prosthetic group.
  • Be familiar with the terms: glycoprotein, lipoprotein, nucleoprotein, phosphoprotein, metalloprotein, hemoprotein, flavoprotein.

Quaternary Structure

What are the forces driving quaternary association?

  • Typical Kd for two subunits: 10-8 to 10-16M!
  • These values correspond to energies of 50-100 kJ/mol at 37 C
  • Entropy loss due to association - unfavorable
  • Entropy gain due to burying of hydrophobic groups - very favorable!
what are the structural and functional advantages driving quaternary association
What are the structural and functional advantages driving quaternary association?

Know these!

  • Stability: reduction of surface to volume ratio
  • Genetic economy and efficiency
  • Bringing catalytic sites together
  • Cooperativity