IMC 05: Proteins as Targets for Drug Molecules

Question 1

Are carbohydrates water soluble?

Answer 1

yes

Question 2

What is the general structure of carbohydrates?

Answer 2

Cn H2n On

Question 3

What are glycoconjugates?

Answer 3

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

Question 4

What are enzymes?

Answer 4

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

Question 5

What are receptors?

Answer 5

proteins that receive and transduce biochemical signals

• typically, receptors have distinct pockets that can be targeted with drug molecules

Question 6

What are scaffolding proteins?

Answer 6

proteins that provide structural integrity and/or help orient other proteins into complexes

Question 7

How many important resonance structures do amide bonds have?

Answer 7

2

• normal one
• negative charge on O + positive charge on N

Question 8

What are the two general orientations of peptide bonds?

Answer 8

• cis
• trans

Question 9

Which peptide bond orientation does steric clash favour?

Answer 9

trans amide

• resonance structures allow for flipping

Question 10

What restricts the folding patterns of polypeptide chains that make up proteins?

Answer 10

combination of:
- double bond character
- amino acid side chains

Question 11

Peptide/Amide Bond

Double Bond Character of C-N Bond

Answer 11

renders amide bonds hydrolytically stable when planar

Question 12

Peptide/Amide Bond

Electronegativity

Answer 12

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

Question 13

Peptide/Amide Bond

Ester Functional Group Stability vs. Amides

Answer 13

ester functional groups are much less stable in aqueous environments than amides

Question 14

Peptide/Amide Bond

Can amide bonds be cleaved?

Answer 14

yes – but generally require an enzyme to catalyze this reaction

Question 15

Primary Structure of Proteins

Answer 15

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

Question 16

Secondary Structure of Proteins

Answer 16

local regions of ordered structure adopted by the protein chain (ie. alpha helices, beta sheets)

• beta strand, beta sheet
• alpha helix

Question 17

Secondary Structure

What is a hydrogen bond?

Answer 17

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

Question 18

Secondary Structure

Hydrogen Bond Donor (HBD)

Answer 18

has a δ+ hydrogen atom – gives away the H atom

Question 19

Secondary Structure

Hydrogen Bond Acceptor (HBA)

Answer 19

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

Question 20

Secondary Structure

Alpha Helices

Answer 20

• 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

Question 21

Secondary Structure

What amino acids is generally not found in alpha helices? (2)

Answer 21

• proline – proline R group forces an incompatible geometry
• glycine – due to high flexibility

Question 22

Secondary Structure

Beta Sheets

Answer 22

• 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

Question 23

Tertiary Structure of Proteins

Answer 23

overall 3D shape
- how the secondary structures and disordered regions are arranged

Question 24

Quaternary Structure of Proteins

Answer 24

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

Question 25

What are common post-translational modifications of proteins?

Answer 25

- phosphorylation of Tyr and Ser by kinases - dephosphorylation by phosphatases

Question 26

Chirality What is chirality?

Answer 26

property of chemical compounds that are non-superimposable on their mirror image - carbon atom with 4 different substituents will usually be a chiral centre

Question 27

Chirality What are enantiomers?

Answer 27

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

Question 28

Chirality How do planes of symmetry affect chirality?

Answer 28

can make things non-chiral even if they have a carbon atom with 4 different substituents – referred to as meso compounds

Question 29

Chirality What are diastereomers?

Answer 29

isomers that have more than one chiral centre and will have different chemical and physical properties compared to their diastereomers

Question 30

Chirality

Answer 30

- 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

Question 31

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?

Answer 31

diastereomers

Question 32

Ionic Interactions

Answer 32

- 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

Question 33

What are the 3 types of van der Waals forces?

Answer 33

- dipole-dipole - ion-induced dipole - dipole-induced dipole - London dispersion force

Question 34

Dipole-Dipole

Answer 34

involves interactions between δ+ and δ- ie. hydrogen bonding

Question 35

Ion-induced Dipole or Dipole-induced Dipole

Answer 35

ions or partial charges will induce dipoles by attracting or repelling electrons in the electron cloud

Question 36

London Dispersion Forces

Answer 36

(weakest) temporary dipole-induced dipole - because electron density is probabilistic, partial charges may result from random electron movement which can also induce dipoles

Question 37

Hydrophobic Interactions

Answer 37

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

Question 38

π -π stacking (pi-stacking)

Answer 38

- 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

Question 39

cation- π interaction

Answer 39

cations (+) can interact with the delocalized electron (-) cloud a benzene ring

Question 40

What is protein folding governed by?

Answer 40

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

Question 41

What is the dielectric constant (D)?

Answer 41

measure of the polarity of a solvent or molecular environment

Question 42

Hydrogen bonds are a strong form of _________________.

Answer 42

dipole-dipole interactions

Question 43

Ionic interactions are _________ in hydrophobic environments.

Answer 43

stronger (even stronger than hydrogen bonds)

Question 44

Entropy of Protein Folding What are the 2 conflicting levels of disorder?

Answer 44

- primary structure goes from disordered to highly ordered (decrease ΔS → increase ΔG) - H2O network that solubilizes the protein sequence

Question 45

Entropy of Protein Folding What is the hydrophobic collapse?

Answer 45

describes a hydrophobic core forming and excluding H2O molecules - entropically driven

Question 46

Entropy of Protein Folding Hydrophobic interactions in the protein core _______________.

Answer 46

exclude highly ordered H2O molecules (increases ΔS → decreases ΔG) - hydrophobic residues get inside to the centre by entropy