W10.2_Interactions between Molecules

Question 1

What is the general purpose of intermolecular forces? How are the properties of amino acids determined?

Answer 1

• Intermolecular forces: stabilises receptor shape in water (3D) -> determines how small molecules interact with receptor/protein
• Amino acids: properties depends on R (side chain) group, can be hydrophobic/hydrophilic/bulky/flexible

Question 2

What are the different categorisations of amino acids? What are the different diagrams used to illustrate the structure of tertiary and quaternary structure of proteins? Explain how DNA has a receptor structure.

Answer 2

• Different categorisation: polar, acidic, basic, non-polar, aromatic, achiral, thiol, cyclic
• Different diagrams for tertiary/quaternary structure: known from spectroscopy (X-ray)
• Ball-and-stick: covalent bonds
• Backbone trace: N-terminus (blue) to C-terminus (red)
• Cartoon: show secondary structure
• Kinase structure: shows specific 3D site into which drugs bind
• DNA as receptor structure: ∵ base stacking -> sugars as inner layer (hydrophilic), DNA bases as ring (hydrophobic), phosphate groups as outer layer (hydrophilic)

Question 3

Explain the properties of hydrogen bonds and its relationship with drug molecules and amino acids. Define Wallace’s rule.

Answer 3

• Hydrogen bonds: X-H ***** Y, where X and Y are highly electronegative
• Orientation-dependent (if angle deviates from 180o, bond weakens)
• Mainly dipole-dipole interaction as basis
• Peptide bond has a stronger H-bond, interactions with charged molecules are even stronger
• Wallace’s rule: in short DNA segments (≤20 base pairs), T(M) = 2(A+T)+4(G+C)
• T(M): temperature (C) when DNA duplex separates/melts into strands
• ∵ There are 2 H-bonds between AT and 3 H-bonds between CG
• Many drugs contain H-bond donor & acceptor
• Possible amino acids: polar, acidic, basic, M, Y, W, C

Question 4

Explain the properties of ionic interactions and its relationship with drug molecules and amino acids.

Answer 4

• Ionic interactions/salt bridges: electrostatic interactions
• Strength of interactions falls at long-range distance -> can be used for recognition
• Drugs can have acidic/basic group that ionises at physiological pH/permanently charged
• Possible amino acids: acidic, basic, C

Question 5

Explain the properties of van der Waals’ interactions and its relationship with drug molecules and amino acids.

Answer 5

• Van der Waals’ interactions/packing interactions: seek to maximise empty space
• Correlation of neighbouring electron clouds -> short-range
• Possible amino acids: all
• When aromatic rings pack together, π-π stacking occurs
• Bigger rings have greater interaction, can occur in aromatic amino acids, DNA bases, ligands
• Orientations: parallel < T-shaped (H-π) < parallel-displaced

Question 6

Explain the properties of hydrophobic effect and its relationship with drug molecules and amino acids.

Answer 6

• Water effects on drug-receptor binding: for high logP/hydrophobic drugs
• Non-polar: ligand and receptor lose unfavourable interactions with water -> causing hydrophobic effect (water is energetically more favourable when H-bond network is not disrupted by non-polar surfaces of ligand/receptor)
• Polar: ligand and receptor lose favourable interactions with water -> smaller net salt bridge interaction

Question 7

Explain the properties of covalent bonding and its relationship with drug molecules and amino acids.

Answer 7

• Covalent bonding: very strong, very prolonged/irreversible pharmacological action
• ex. penicillin binds to serine residue of transpeptidase -> inactive -> X form structural cross-linking of bacterial cell wall -> weakens cell -> bursts and dies
• Can be seen in organo-phosphate insecticides (ex. parathion) and chemical weapons (ex. Sarin, VX, Novichoks)