IMC 05: Proteins as Targets for Drug Molecules Flashcards
Are carbohydrates water soluble?
yes
What is the general structure of carbohydrates?
Cn H2n On
What are glycoconjugates?
glycoproteins or glycolipids that serve as molecular tags important in cell recognition
- these tags can commonly act as antigens when introduced into a different individual
What are enzymes?
proteins that catalyze chemical reactions
- deep cavities or pockets that make up their ‘active sites’ where chemical transformations take place
- these pockets can be targeted with drug molecules
What are receptors?
proteins that receive and transduce biochemical signals
- typically, receptors have distinct pockets that can be targeted with drug molecules
What are scaffolding proteins?
proteins that provide structural integrity and/or help orient other proteins into complexes
How many important resonance structures do amide bonds have?
2
- normal one
- negative charge on O + positive charge on N
What are the two general orientations of peptide bonds?
- cis
- trans
Which peptide bond orientation does steric clash favour?
trans amide
- resonance structures allow for flipping
What restricts the folding patterns of polypeptide chains that make up proteins?
combination of:
- double bond character
- amino acid side chains
Peptide/Amide Bond
Double Bond Character of C-N Bond
renders amide bonds hydrolytically stable when planar
Peptide/Amide Bond
Electronegativity
the more electronegative oxygen atom of the ester is less willing to donate its lone pair to the double bond than the nitrogen atom of the amide
Peptide/Amide Bond
Ester Functional Group Stability vs. Amides
ester functional groups are much less stable in aqueous environments than amides
Peptide/Amide Bond
Can amide bonds be cleaved?
yes – but generally require an enzyme to catalyze this reaction
Primary Structure of Proteins
the order in which individual amino acids that make up a protein are linked together via peptide bonds
- responsible for distinct folding (2º structure), shape (3º structure), and protein-protein interactions (4º structure)
- dictates protein folding – changing primary structure can change everything else
Secondary Structure of Proteins
local regions of ordered structure adopted by the protein chain (ie. alpha helices, beta sheets)
- beta strand, beta sheet
- alpha helix
Secondary Structure
What is a hydrogen bond?
non-covalent interaction that occurs between a heteroatom (usually oxygen or nitrogen) and a hydrogen atom attached to another heteroatom
- subtype of dipole-dipole interactions
- differences in electronegativity make hydrogen atoms δ+ and heteroatoms δ- (N and C)
- partially positive (δ+) hydrogen atoms will interact with lone pairs on N and O to make hydrogen bonds
Secondary Structure
Hydrogen Bond Donor (HBD)
has a δ+ hydrogen atom – gives away the H atom
Secondary Structure
Hydrogen Bond Acceptor (HBA)
is δ- and has a lone pair in a hybrid orbital – accepts the H atom, has a lone pair
- ie. not involved in aromatic pi system
Secondary Structure
Alpha Helices
- held in place by hydrogen bonding between residues in protein backbone – NOT side chains
- 3.6 residues per helix turn of the helix (residues n, n+4, and n+7 on same side)
- hydrophobic alpha helices can span membranes
Secondary Structure
What amino acids is generally not found in alpha helices? (2)
- proline – proline R group forces an incompatible geometry
- glycine – due to high flexibility
Secondary Structure
Beta Sheets
- anti-parallel beta sheets (common) have good overlap of h-bonding (180º angle)
- parallel beta sheets (less common) have angled H-bonds (weaker)
- sequential amino acid R-groups are arranged on opposite sides of the sheet
- can form additional structures such as beta turns and beta barrels
Tertiary Structure of Proteins
overall 3D shape
- how the secondary structures and disordered regions are arranged
Quaternary Structure of Proteins
arrangement of proteins in a multi-protein complex
- how the tertiary structures are arranged in complexes
- may be multi-component structures or oligomers of one protein
What are common post-translational modifications of proteins?
- phosphorylation of Tyr and Ser by kinases
- dephosphorylation by phosphatases
Chirality
What is chirality?
property of chemical compounds that are non-superimposable on their mirror image
- carbon atom with 4 different substituents will usually be a chiral centre
Chirality
What are enantiomers?
chiral isomers with one chiral centre
- have the same chemical and physical properties as each other
- differ only by how they interact with other chiral compounds and with light
Chirality
How do planes of symmetry affect chirality?
can make things non-chiral even if they have a carbon atom with 4 different substituents – referred to as meso compounds
Chirality
What are diastereomers?
isomers that have more than one chiral centre and will have different chemical and physical properties compared to their diastereomers
Chirality
- chiral molecules are non-superimposable on their mirror image
- enantiomers may interact with chiral molecules differently
- enantiomers interact with light differently
- carbon atom with 4 different substituents is often a chiral center
If a pair of compounds that are chiral isomers (mirror images of each other) have different melting temperatures, what term is best to describe these isomers?
diastereomers
Ionic Interactions
- especially important in hydrophobic environments (active sites and hydrophobic protein core)
- on the protein surface, ions interact with water molecules (ion-dipole interactions) which are stabilizing
What are the 3 types of van der Waals forces?
- dipole-dipole
- ion-induced dipole
- dipole-induced dipole
- London dispersion force
Dipole-Dipole
involves interactions between δ+ and δ-
ie. hydrogen bonding
Ion-induced Dipole or Dipole-induced Dipole
ions or partial charges will induce dipoles by attracting or repelling electrons in the electron cloud
London Dispersion Forces
(weakest) temporary dipole-induced dipole
- because electron density is probabilistic, partial charges may result from random electron movement which can also induce dipoles
Hydrophobic Interactions
describes favourable interactions between two hydrophobic groups in an aqueous environment
- interaction of hydrophobic groups reduces hydrophobic surface area and reduces the area of highly ordered water matrix
- major driving force for protein folding and for drug binding to protein active sites
π -π stacking (pi-stacking)
- delocalized pi system increases electron density above and below the aromatic ring
- carbon atoms in the ring are therefore δ+
- weaker than van der waals forces – small role in protein folding
- control substrate and drug binding properties
cation- π interaction
cations (+) can interact with the delocalized electron (-) cloud a benzene ring
What is protein folding governed by?
Gibbs free energy: ΔG = ΔH - T ΔS
- ΔG: change in the free energy – if ΔG < 0 then process is spontaneous (ie. protein folding)
- ΔH: change in enthalpy – energy stored in covalent (disulfide bridges) and non-covalent bonds
- ΔS: change in entropy – term for the relative disorder (disorder = favoured)
- T: temperature
What is the dielectric constant (D)?
measure of the polarity of a solvent or molecular environment
Hydrogen bonds are a strong form of _________________.
dipole-dipole interactions
Ionic interactions are _________ in hydrophobic environments.
stronger
(even stronger than hydrogen bonds)
Entropy of Protein Folding
What are the 2 conflicting levels of disorder?
- primary structure goes from disordered to highly ordered (decrease ΔS → increase ΔG)
- H2O network that solubilizes the protein sequence
Entropy of Protein Folding
What is the hydrophobic collapse?
describes a hydrophobic core forming and excluding H2O molecules
- entropically driven
Entropy of Protein Folding
Hydrophobic interactions in the protein core _______________.
exclude highly ordered H2O molecules (increases ΔS → decreases ΔG)
- hydrophobic residues get inside to the centre by entropy
