Patrick, An Introduction to Medicinal Chemistry 4e Chapter 2 Proteins: structure and function Answers to end-of-chapter questions 1)

O H2N Me N H O Ph H N O OH

2) Glycine is the only amino acid with no side chain and is the only naturally occurring amino acid that is not asymmetric. 3) Possible interactions are shown below for the side chains of serine, phenylalanine, glycine, lysine and aspartic acid (HBA= hydrogen bond acceptor; HBD = hydrogen bond donor; vdw = van der Waals interactions)
Serine H2N H CO2H R= O HBA H HBD H vdw No side chain Glycine

Phenylalanine

R Amino acid structure

Lysine

Aspartic acid HBA O O HBA H HBD

Aspartate HBA O ionic O HBA

R= HBA H HBD N H HBD

N HBDH H H HBD HBD

ionic

4) If a sequence of amino acids with hydrophobic side chains can be identified in the primary structure, it is possible that this is a transmembrane (TM) region of the protein (i.e it is located within the cell membrane as shown below) This is because hydrophobic side chains would interact more favourably with the fatty cell membane than with the aqueous environments on either side of the cell membane. Regions of the protein that are made up predominantly of polar side chains are almost certainly located intracellularly or extracellularly. However, it would be wrong to conclude that all amino acids with hydrophobic side chains are located in transmembrane regions and all amino acids with polar side chains are located intracellularly or extracellularly.

OXFORD H i g h e r E d u c a t i o n Oxford University Press, 2009. All rights reserved.

Patrick, An Introduction to Medicinal Chemistry 4e Chapter 2 Proteins: structure and function

H2N Extracellular loop CO2H

TM1 TM2 Intracellular loop

TM3

TM4

Cell membrane

Intracellular loop

5) The structure of L-alanyl-L-valine is shown below.

H2N H O N CH3 H CO2H

An attempt to couple alanine directly to valine may well produce the desired product but a whole range of other structures will also be formed.
H2N H CO2H H2N + H3C CH3 H CO2H H2N H O N CH3 H CO2H + many other peptides

CH3

For example, L-valyl-L-alanine is an equally likely product. There is also nothing to stop alanine coupling with itself, or valine coupling with itself to form L-alanyl-Lalanine and L-valyl-L-valine respectively. Furthermore, there is no reason why any of the above dipetides that are formed could not undergo a further coupling reaction to form tripeptides, tetrapeptides etc. The reaction is also likely to need forcing conditions since one is attempting to form an amide between an amine and a carboxylic acid which are more likely to form a salt at room temperature. Forcing conditions are likely to result in racemisation of asymmetric centres. Due to these problems, it is necessary to protect the amino group of one amino acid and the carboxylic acid of the other before a coupling reaction is attempted. It is also important to have coupling reagents (e.g. dicyclohexylcarbodiimide) in order to achieve milder, non-racemising conditions. 6) The functional groups involved are alcohols and phenols. Both of these functional groups can form hydrogen bonds. When the groups are phosphorylated, the phosphate groups are ionised and will interact with ionic groups rather than hydrogen bonding groups.

OXFORD H i g h e r E d u c a t i o n Oxford University Press, 2009. All rights reserved.

Patrick, An Introduction to Medicinal Chemistry 4e Chapter 2 Proteins: structure and function

H2N H CO2H R= HBA O HBD H alcohol Phosphorylation H O H HBD HBD H O HBA phenol Phosphorylation Serine Threonine Tyrosine

CH3 HBA

alcohol

Phosphorylation

O O O P O O Ionic H O CH3 P

O O

Ionic O Ionic O O P O

The tertiary structure will alter as a result (see section 5.2.6). 7) Glu-Leu-Pro-Asp-Val-Val-Ala-Phe-Lys-Ser-Gly-Gly-Thr The one letter coding is ELPDVVAFKSGGT

OXFORD H i g h e r E d u c a t i o n Oxford University Press, 2009. All rights reserved.