Lecture 2: Amino acids and peptides

Reading: Chapter 3 pp. 75-89

Proteins carry out most of the activities in all cells

Bacterial cell

Human liver

Proteins are polymers of amino acids

This C is called the -carbon

There are 20 common amino acids that make up almost all proteins. Each has a carboxyl group and an amino group bonded to the same carbon atom. Each has a different side chain, or R group.

Tetrahedral arrangement of bonding orbitals around the -carbon atom

For all the common amino acids except glycine,the -carbon is bonded to 4 different groups: a carboxyl group, an amino group, an R group and an H atom. The -carbon is therefore a chiral center; the four different groups can occupy two unique spatial arrangements.

Enantiomers of alanine

Since they are nonsuperimposable mirror images of each other, the two forms represent a class of stereoisomers called enantiomers.

Different ways of representing enantiomers

Special nomenclature is used to specify the absolute configuration of the 4 substituents of asymmetric carbon atoms. We use the D, L system based on the absolute configuration of the 3 carbon sugar glyceraldehyde, a convention proposed by Emil Fischer in 1891.

Similarity to glyceraldehyde is used to designate configuration

The amino acids in proteins are exclusively L stereoisomers.

How would a peptide made of D amino acids behave?

Peter Kim, currently the Vice President for Research at Merck, wondered whether such unnatural peptides would be useful as therapeutics in cells or serum, where L-peptides are quickly destroyed by naturally occurring enzymes. While a faculty member at the Whitehead Institute at MIT, Kim and his coworkers synthesized an HIV protein in the D-amino acid configuration and used it to identify L-amino acid peptides that bind to it specifically. For reasons of symmetry, the mirror images of these L-amino acid peptides interact with the target protein of the natural handedness. Thus, it was possible to produce the enantiomeric D-amino acid peptides that recognized the natural target protein while avoiding degradation by enzymes that act upon natural peptides. This approach was subsequently used to make D-peptide based drugs that inhibit the entry to the AIDS virus HIV-1 into cells.
To read the original paper: Schumacher et al. (1996) Identification of D-peptide ligands through mirror-image phage display. Science 271:1854

Amino acids can be classified by R group

Amino acids can be classified by R group

These side chains are nonpolar and hydrophobic. Ala, Val, Leu and Ile tend to cluster together within proteins, stabilizing protein structure via hydrophobic interactions.

Phe, Tyr and Trp are relatively hydrophobic. The hydroxyl group of Tyr can form hydrogen bonds and plays an important functional role in some enzymes. Tyr and Trp (and to a much lesser extent, Phe) absorb uv light. This accounts for the characteristic strong absorbance of light by most proteins at a wavelength of 280 nm, a property useful in protein purification and analysis.

Absorbance of uv light by Trp, Tyr

This graph shows the absorbance spectra of the amino acids Tyr and Trp, present in equal amounts under identical conditions. The measured absorbance of Trp is about four times greater than that of Tyr. Note that the absorbance maximum is close to 280 nm in each case.

The R groups of these amino acids are more hydrophilic because they contain functional groups that form H bonds with water. Asn and Gln are amides of two other common amino acids, aspartate and glutamate.

Cysteine can oxidize to form a covalently linked dimeric amino acid, cystine

The most hydrophilic R groups are those that are either positively or negatively charged. Lys, Arg and His have significant positive charge at pH 7.0. Note that His is the only amino acid with an ionizable side chain that has a pKa near neutrality. Because of this, His serves as a proton donor or acceptor in many enzyme-catalyzed reactions.

Two amino acids, Asp and Glu, have R groups with a net negative charge at pH 7.0. Each has a second carboxyl group.

You must memorize the 20 common amino acids

You will need to know the chemical structures of the amino acids and their chemical properties. You also need to know the three-letter and single-letter codes for the amino acids

The origin of the single-letter code for the amino acids

In the early days of bioinformatics,even the fastest computers were pretty pokey. Dr. Margaret Dayhoff, a leader in the application of mathematics and computing to the field of biochemistry, shortened the code from three to one letter in order to reduce the size of the data files needed to describe protein sequences. For 6 of the amino acids, the first letter of the name is unique and hence the code is simple:

Cysteine Histidine Isoleucine Methionine Serine Valine

Cys His Ile Met Ser Val

C H I M S V

The origin of the single-letter code for the amino acids

For the other amino acids, the first letter of the name is not unique to a single amino acid. Dr. Dayhoff assigned the letters A, G, L, P and T as follows:

Alanine Glycine Leucine Proline Threonine

Ala Gly Leu Pro Thr

A G L P T

These amino acids occur more frequently in proteins than do the other amino acids having the same first letters.

The origin of the single-letter code for the amino acids

Some of the other amino acids, are phonetically suggestive:

Arginine Phenylalanine Tyrosine Tryptophan Aspartic acid Asparagine Glutamic acid Glutamine Lysine

Arg Phe Tyr Trp Asp Asn Glu Gln Lys

R F Y W D N E Q K

Twyptophan

asparDic asparagiN glutamEke Q-tamine (K is near L in alphabet)

Uncommon amino acids also have important functions

Many, like these, are created by modification of common amino acids after incorporation into a protein. Both of these are found in collagen, a fibrous protein of connective tissues.