Lecture 4: Biological Targets and Their Modulation

Biological molecules are modular

• Protein:

  • Linear chain of Amino acids

  • Amide bonds

• Nucleic acids:

  • Linear chain of nucleotides

  • Phosphate ester

• Polysaccharides:

  • Liner chains of sugars, some are branched

  • Acetals

• Lipids

  • Linear chains of acetate or propionate

  • Chain is modified so the assembly units are hidden

  • Reduce aldol (1,3 - dicarbonyl)

Modular construction makes life possible

• Easily assemble complex structures using simple molecules components

• Easily disassemble complex structures and regenerate parts for reuse

• Only need 1 enzyme system for each biomolecule type and function

  • Proteins made by ribosome

  • Protein disassembled by proteasome

Drugs produce effects by binding to biomolecules

• Proteins are the most common target

  • Nucleic acids are less common

• Drugs produce effects by binding to biological molecules 

Biomolecules have well-defined 3-D shapes

• They create three dimensional chemical environments

• Drugs interact with biological molecules in 3-D way

• The shape and pattern of electron density determine binding

  • Non-covalent interactions

• Some drugs react chemically with biological molecules

  • Covalent bonds

Proteins are made of amino acids

• 20 different canonical types of amino acid are used

  • Occasionally, some proteins contain modified or unusual amino acids

• Amino acids share the same backbone and stereochemistry, but differ in their side chains (R) 

• The chemical properties of side chains vary, contributing to the diverse functions of proteins

Amino acid side chain properties 

Amino acid side chain properties 

Peptides are linear chains of amino acids

• Proteins are long peptides folded into a particular shape

Nucleophilic substitution of carboxylate

Amide Bond formation - Base catalysis

Amide bond formation - Acid catalysis 

Primary structure of proteins 

• Sequence of amino acids in a protein

  • (this is the only information specified by a gene)

• Amino acids are joined by peptide bonds (amide bonds)

Primary structure is a list

• By convention, amino acids in a protein are listed in order from the N-terminus towards the C-terminus

Secondary structure

• Regions of local order in the backbone chain

• Forms small-scale structures such as:

  • A- helix

  • B- helix

  • Loop 

  • Turn

• Represented in ribbon structures

Origin of secondary structure

• Conformational restrictions in amide bonds

• Conformation restrictions between amide and a-carbon

• Interactions between amide bonds

  • Intermolecular forces acting in an intramolecule way

  • Same forces that control solubility

• Side chain interactions within a region of the chain

Amide bond has double bond character

Side chain interactions

• Negative charges attract positive charges

• Hydrogen bonding between side chains and backbones

• Non-polar side chains interact with other non-polar chain - steric interactions

• The result of these chemical interactions is the folding of the amino acid chain to produce large-scale structures

B- structures

• B-stands

  • Backbone atoms are coplanar or “flat’

• Several strands can associate to form sheets (B-sheet)

• Large sheets can curl around themselves, forming cylinders (B-barrels

B- sheet can be parallel or antiparallel

Loops

• Areas with no defined secondary structure

• Represented by “spaghetti” on ribbon diagrams

Turns

• Several types

• May not be explicitly represented on ribbon diagrams

• Look for areas where the chain changes direction by a large amount

Tertiary structure

• Overall 3-D shape of a protein

• Result on interactions between non-adjacent regions

  • Amino acid side chains

  • 2 secondary structures (two helices)

• Contains regions of order

  • Secondary structure

• Contains less ordered regions

  • Loops

Tertiary structure and attractive forces

• Attractions between secondary structures cause the secondary structures to folf back on themselves

• These are mostly non-bonding interactions

• There are occasional covalent bonds

Van Der Waals interactions are very important 

Dipole interactions and H-bonds stronger Inside Hydrophobic environment

• Non polar environment critical to holding protein together

Some proteins form Quaternary structures

• Two or more proteins bind together

• Sub units can be the same or different

Protein-Protein interactions are very strong

• Lots of surface contact area

• Lots of chemical interactions

• Exclusion of water from space between

• Proteins stick together well

• Difficult to separate some proteins

Overall structures determine function

• Most of the molecule is a scaffold

• Only a small part is normally “functional”

Identify the correct structure based on the sequence below