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Advanced A Level Organic Chemistry: ISOMERISM - Peptides, combinational chemistry

dipeptide GlyAla (c) doc b

Doc Brown's Advanced A Level Organic Chemistry Revision Notes - Help in Revising Advanced Organic Chemistry

PART 14 ORGANIC ISOMERISM

and Stereochemistry Revision Notes

14.5 Protein analysis & synthesis AND combinatorial chemistry and autosynthesis


INDEX of isomerism & stereochemistry of organic compounds notes

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Combinatorial chemistry and autosynthesis:

COMBINATORIAL CHEMISTRY - definition - Combinatorial chemistry can be defined as the synthesis of different chemical compounds as ensembles ('libraries') and the immediate (maybe 'in-situ') screening of them for desirable properties. Combinational  chemistry is potentially an efficient route to new drugs, catalysts, and other compounds and new materials.


dipeptide AlaGly (c) doc bProtein Synthesis - possible peptide structures

For more details see also Part 6.13 Amino acids - molecular structure, preparation and reactions - two functional group chemistries, polypeptide formation and hydrolysis and chromatographic analysis

(On this page I'm only repeating the basic ideas on peptide formation and structure, best to read 6.13 first)

Two theoretical combinations of two different alpha amino acids, differing only in the R and R' groups to form a dipeptide.

H2N-CHR-COOH + H2N-CHR'-COOH (c) doc b

{H2N-CHR-CO-NH-CHR'-COOH or H2N-CHR'-CONH-CHR-COOH} + H2O

Note:

This is a condensation reaction, because a small molecule (water) is eliminated as the two molecules join to form a bigger molecule, a 'natural condensation polymer' and hence the name 'polypeptide' for a protein structure.

 -NH-CO- is the secondary amide 'peptide linkage' and the reaction is illustrated below with aminoethanoic acid, (glycine) and 2-aminopropanoic acid (alanine) showing the two possible di-peptide products (GlyAla or AlaGly).

In this case, both dipeptides have one chiral carbon, >CH-CH3 and >CH-NH2 respectively.

Since each of the two possibilities is stereochemically different, not surprisingly, you would expect a different enzyme (with cofactor?) for each alternative synthesis.

aminoethanoic acid (glycine) (c) doc b 2-aminopropanoic acid (alanine) (c) doc b

 dipeptide GlyAla (c) doc b    or    dipeptide AlaGly (c) doc b      H2O

In abbreviated structural formula style, the reaction in terms of possible zwitterions would be ...

 +H3NCH2COO- + +H3NCH(NH2)COO- ==> {+H3NCH2CONHCH(CH3)COO- or  +H3NCH(CH3)CONHCH2COO-} + H2O

 

The sweetener aspartame is a dipeptide formed from the two amino acids phenylaniline and aspartic acid.

C6H5CH2CH(NH2)COOH  + HOOCCH2CH(NH2)COOH  ===> C6H5CH2CH(NH2)CONHCH(COOH)CH2COOH  +  H2O

If they were combined the other way round, the dipeptide might not be sweet at all!

 

A more complex situation is tabulated below, showing the nine possible dipeptides that can theoretically be formed from just from three different amino acids.

The possibilities are greatly expanded if the permutations of tripeptides etc. were to be considered, and this ignores chiral isomers!

Possible amino acids X and Y, and possible XY di-peptides formed Y = A1 Y = A2 Y = A3
X = A1 A1A1 A1A2 A1A3
X = A2 A2A1 A2A2 A2A3
X = A3 A3A1 A3A2 A3A3

These days it is possible to 'automatically' synthesise polypeptides in a 'peptide synthesiser' into which, the required reactants are fed in a pre-programmed way, so all sorts of permutations can be prepared.

The polypeptides can be prepared or 'grown' on polystyrene beads - an example of solid phase chemistry.

This has positive 'efficiency' implications for the pharmaceutical industry e.g. some polypeptides are used as drugs and their structure is effectively a 'mini-protein'.

It is possible to synthesise a huge variety of permutations using this combinational chemistry, analyse them to validate their structure and then test them for their biological/pharmacological activity.

This idea can be used for a variety of organic synthesis, not just for amino acids ===> polypeptide, and this, since the 1990's is speeding up the development of drugs and other biologically active molecules.


Protein hydrolysis - broken down into their constituent amino acids - analysis

Proteins-polypeptides can be broken down by hydrolysis.

In principle, the complete hydrolysis reaction for a polypeptide of n residues is ...

-(HN-CHR-CO-)n- + nH2O ==> n H2NCHRCOOH (but remember, R varies from amino acid to amino acid residue)

The complete hydrolysis into the constituent alpha-amino acids can be achieved by heating the protein with 5-6M hydrochloric acid in a sealed tube at 100-120oC, for 10-24 hours.

A partial and selective/specific hydrolysis into short peptide sequences can be done under much milder conditions using enzymes such as the protease trypsin, found in the small intestine.

There are other much more elaborate methods involving chemical modification of the terminal amino acid residue, to obtain specific amino acid residue sequencing, but these are well beyond the scope of this web page (i.e. UK GCE courses). The resulting hydrolysis mixture can be analysed by e.g.

(i) paper/thin layer chromatography, often in two dimensions using two different solvents (paper rotated 90o between solvents). The colourless amino acids can be made visible by spraying the chromatography paper/plates with ninhydrin reagent. Purple spots show up from the coloured compound formed from the combination of the amino acid with ninhydrin.

For more details see 6.13 Amino acids - molecular structure, preparation and reactions including chromatography

(ii) electrophoresis, in which the ionic forms of the amino acids are separated by movement in a buffered aqueous gel medium under the influence of an applied electric field (from d.c. voltage electrodes). The different amino acid mobilities depend on the average total +ve or -ve charge in a particular buffer.

The amino acids form bands which can be detected-analysed by using staining techniques or uv light fluorescence. The technique can also be applied to the analysis of protein or nucleic acid mixtures, and the latter can be detected using a radioactive phosphorus tracer 32P (in the laboratory you should only deal with stable 31P).

In all cases the techniques can be calibrated using pure samples of known amino acids, proteins or nucleic acids etc.


More on Combinatorial Chemistry

What is combinational chemistry and what can it do?

  • Combinatorial chemistry is a means of automatically synthesising a range of different chemical compounds from ensembles called 'libraries' and the efficient screening of the different molecular 'combinations' for desirable properties which maybe materials with physically desirable properties or drugs with particular advantageous pharmacological properties.

  • The laboratory synthesis of polypeptides has already been described above and the same principles can also be applied to the synthesis of drugs.

  • The 'active' or 'interacting' part of a molecule is called pharmacophore group and changing its nature and the associated 'molecular architecture' around it, may improve or change its pharmacological activity.

    • A pharmacophore is a group of atoms which confers pharmacological activity on a molecule.

  • It is possible to rapidly, and automatically, synthesise lots of variations from selected to reactants and then screen the products for their pharmacological activity.


Doc Brown's Advanced Level Chemistry Revision Notes

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INDEX of isomerism & stereochemistry of organic compounds notes

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