Patrick, An Introduction to Medicinal Chemistry 4eChapter 2 – Proteins: structure and function

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

Answers to end-of-chapter questions

1)

H2NNH

HN

OH

O

O

O

Me

Ph

2) Glycine is the only amino acid with no side chain and is the only naturallyoccurring 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 = hydrogenbond donor; vdw = van der Waals interactions)

H2N CO2H

R

H

Amino acidstructure

Serine

R=

Phenylalanine Glycine

Lysine Aspartic acid

O

H

H

O O

HBA

HBDvdw No side

chain

NH H

NH H

H

R=O

H

O

ionicHBA

HBD HBD HBDHBD

HBD

HBD

HBA

HBA

HBA

ionic

Aspartate

HBA

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

Patrick, An Introduction to Medicinal Chemistry 4eChapter 2 – Proteins: structure and function

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

H2N

CO2H

TM1 TM2

Extracellularloop

TM4TM3

Intracellularloop

Cellmembrane

Intracellularloop

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

H2N

CH3

H

N

O

CO2H

HH

An attempt to couple alanine directly to valine may well produce the desired productbut a whole range of other structures will also be formed.

H2N CO2H

H3C CH3

HH2N CO2H

CH3

H

H2N

CH3

H

N

O

CO2H

HH

+ many other peptides+

For example, L-valyl-L-alanine is an equally likely product. There is also nothing tostop alanine coupling with itself, or valine coupling with itself to form L-alanyl-L-alanine and L-valyl-L-valine respectively.Furthermore, there is no reason why any of the above dipetides that are formed couldnot undergo a further coupling reaction to form tripeptides, tetrapeptides etc.The reaction is also likely to need forcing conditions since one is attempting to forman amide between an amine and a carboxylic acid which are more likely to form a saltat room temperature. Forcing conditions are likely to result in racemisation ofasymmetric centres.Due to these problems, it is necessary to protect the amino group of one amino acidand the carboxylic acid of the other before a coupling reaction is attempted. It is alsoimportant to have coupling reagents (e.g. dicyclohexylcarbodiimide) in order to achievemilder, non-racemising conditions.

6) The functional groups involved are alcohols and phenols. Both of these functionalgroups can form hydrogen bonds. When the groups are phosphorylated, thephosphate groups are ionised and will interact with ionic groups rather than hydrogenbonding groups.

Patrick, An Introduction to Medicinal Chemistry 4eChapter 2 – Proteins: structure and function

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

H2N CO2H

R

H

R=

Serine Threonine Tyrosine

O

H

H

OH

alcohol

OH

CH3

alcohol phenol

HBAHBA

HBA

HBD

HBDHBD

Phosphorylation Phosphorylation Phosphorylation

O

P

H

OP

OP

CH3O O

O

O

OO

O

OO

Ionic

Ionic

Ionic

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