Ch 3: Amino Acids and Peptides

General Amino Acid Structure

 Understand the basic structure of an amino acid and the designations for the fundamental chemical groups
o Central (alpha) Carbon atom, carboxyl group(s), and amino group(s).
 Alpha Amino group – NH2 functional group.
 It can act as a Bronsted Base by accepting a proton to become ionized into NH3+.
 Alpha carboxyl group – COOH functional group.
 It can act as a Bronsted Acid to release a proton to dissociate into a carboxylate anion –COO—
 Due to their pKa values, carboxyl and amino groups are usually in their ionized form at neutral pH.
 The alpha carbon is also bonded to the alpha hydrogen and a side chain ®.
 Side chain – determines the identify of an aa and confers their unique chemical and bonding properties.
o Because all amino acids have a charged alpha amine (+) and carboxyl groups (-) at pH 7, they are ALL polar.
o The side chain carbons are designated with Greek symbols starting a the alpha carbon.
 Starting at a-carbon (β-, γ-, δ-, ε-, and ω-, last)
 Know the significance of the D- and L- designations
o Know the significance of chirality
 Most amino acids exhibit chirality – this means that they have stereoisomers, or molecules that differ only in configuration.
o –OH of Glyceraldehyde – L/levorotatory rotates polarized light to the left OR D/dextrorotatory rotates to the right
 L and D forms are enantiomers – or nonsuperimposable mirror images
o All amino acids have at least one chiral center; most amino acids have the L configuration.
 Glycine is the only nonchiral amino acid with a simple H as a side chain
 Proline is the only imino acid – the alpha amine group is covalently bound to the sidechain, forming a
cyclic structure.
 Proline is usually in the L form.
 Know the significance of the amino acid side chain
o Classification – Smaller amino acids are represented simply by the first letter of the name
 More complex amino acids have a phonetic symbol, such as arginine ®.
 Know the names, structures, 3-letter, and single-letter abbreviations of the 20 common amino acids
o Know how to classify them as hydrophobic, polar uncharged, or polar charged
o Know the types of functional groups present

Review Exercises Recommended: 1

Amino Acid Structure: Uncharged Side Chains

NONPOLAR – They’re usually located in the interior of a molecule to avoid water interaction.
 Know the structures, etc. of the amino acids with nonpolar side chains – nonpolar based solely on the nature of R group.
o Know how to distinguish them from each other
o Uncharged amino acid are nonpolar and therefore mostly do not interact with water due to their hydrophobicity.
 Amino acids with an aliphatic (hydrocarbon-like) side chain: alanine, valine, leucine, isoleucine, glycine, proline.
o There is a range of non-polarity based on the extent of the surface area of the nonpolar region
 Leucine is more nonpolar than alanine.
o Proline contains an aliphatic cyclic structure – the only imino acid.
 Its aliphatic side chain is covalently bonded to its alpha-amino group.
 Exception: methionine’s Sulfur and tryptophan’s -NH can form some level of hydrogen bonds with water.
 Amino acids with aromatic side chains: hydrocarbon cyclic structure with alternating single and double bonds.
o Phenylalanine, tryptophan, and methionine.
 Phenylalanine – the ring is a simple benzene ring
 Tryptophan – aromatic indole ring.
 Methionine – contains an electronegative Sulfur atom bound to aliphatic hydrocarbons.
 S + aliphatic hydrocarbons makes the side chain nonpolar overall.
 Because hydrophobic amino acids lack reactive side chains, they do not directly participate in mediating chemical reactions.

POLAR – contain hydrogen bonding groups and thus interact with water.
 Know the structures, etc. of the amino acids with polar-neutral side chains – differ from nonpolar amino acids.
o Polar-neutral – serine, threonine, tyrosine, cysteine, glutamine, asparagine.
 Serine and threonine both carry hydroxyl groups bound to aliphatic hydrocarbons
 Tyrosine – aromatic benzene ring that is POLAR and uncharged.
 Its polar b/c it carries a –OH group at the para position of the ring
 Cysteine – carries an end thiol group or a S at the end.
 Glutamine and asparagine contain a terminal amide groups
1
 Ch 3: Amino Acids and Peptides
 Differ in the number of carbons and the aliphatic portion of their side chains.
o VERY polar due to functional groups.
o Know how to distinguish them from each other
 Polar amino acids are found in the solvent-exposed surface of a protein
o They can also occur in the protein interior, provided that their H-bonding requirements are satisfied by their
proximity to other hydrogen bond donor or acceptor groups.

Amino Acid Structure: Charged Side Chains

 Know the structures, etc. of the amino acids with acidic side chains: glutamic acid (glu) and aspartic acid (asp).
o Glu and Asp carry end carboxyl groups in their side chains but differ in the length of the aliphatic portion of R.
 Carboxyl group can readily lose protons (H) at neutral pH to form the carboxylate (–COO—anions)
 The low pKa values of the side chains that makes them acidic and negatively charged.
 Know the structures, etc. of the amino acids with basic side chains: lysine (lys), histidine (his), and arginine (K)
o His, Lys, and Arg side chains are positively charged at or near pH 7
 Lysine – long aliphatic hydrocarbon chain; it also carries an end amine group at the epsilon position
 The amino group (NH3+) has a high pKa value that can readily accept a proton at neutral pH,
thereby becoming ionized.
 Arginine – also has a long aliphatic chain; but the terminal functional group is a guanidino group
 Guanidino group: NH2-C=NH2+
o Guanidine group has the highest pKa value of ALL amino acids: always charged.
 Histidine – side chain is imidazole ring that can be protonated
 Its pKa value is slightly less than neutral yet it can be protonated close to a pH of 7: its basic.
o These positive side chains are usually located on the surface of a protein, where their charged groups can be
surrounded by water molecules or interact with other polar or ionic substances.
 Acidity: alpha-COOH groups and alpha-NH3+
o Average pKa of alpha-carboxyl group is 2.19
 Its MUCH stronger than acetic acid; thus carboxyl group more readily releases its proton
 This occurs b/c of the electron-withdrawing effect of the alpha-amine: close in proximity b/c
they’re both connected to the alpha-carbon.
 Alpha-amine VS a secondary (2O) alkyl ammonium ion: alpha amine is a weaker base due to the influence
of the nearby carboxyl group in its electron donating effect of -COO.
 Thus, pKa values for functional groups are influenced by the local environment.
 Basicity: alpha-NH3+
o Guanidine group of arginine is a stronger base than an aliphatic amine:
 Thus, guanidine pKa is much larger due to resonance stabilization after accepting a proton (pi-way).
o Histidine’s imidazole group is a heterocyclic aromatic amine
 Know that there are amino acid that are uncommon or nonstandard – derived from common amino acids
o Produced through post-translational modifications
 Hydroxylysine and hydroxyproline are found only in few connective tissue proteins such as collagen.
 Thyroxine is derived from tyrosine and is tissue specific, found only in the thyroid gland.
o You do NOT need to know the details of each one
 Depending on the presence of nearby groups that increase their polarity, some polar side chains can ionize at physiological
pH values.
o The basic/neutral form of histidine can accept a proton to form an imidazolium ion (an acid).
 The ability of histidine to act as an acid or a base gives it its great versatility in catalyzing reactions.
o The thiol (S) on cysteine can be deprotonated yielding a thiolate anion.
 Cys’ thiol undergoes oxidation with another thiol group to form a disulfide bridge.
 Glycine is considered polar yet it cannot form hydrogen bonds; its considered polar b/c its neither hydrophobic nor charged.
Review Exercises Recommended: 2, 3, 4, 5, 6

Amino Acids as Acids and Bases

 Understand the concept of zwitterions
o In free amino acids, the negative carboxyl and positive amino group are oppositely charged and therefore electrically
neutral at neutral pH 7.
 Thus, amino acids that lack a charged side chain, exist at pH 7 as zwitterions or twin ions.
o Cation  neutral  anionic
 In the cationic form, the pH is lower than the lowest pKa value (pH<pKa) and is therefore protonated for
every ionizable group.
 As base is added and protons are titrated (-H), the pH becomes equal to the pKa of the alpha-carboxyl.
2
 Ch 3: Amino Acids and Peptides
 Thus, the alpha-carboxyl becomes ½ titrated and thus ½ ionized.
 As the pH increases, the full zwitterionic form is reached: amino acid is electrically neutral overall.
 A further increase in pH causes the pH to equal to the pKa of the amino group: amino is ½ ionized
 At a pH of unit higher than the amino’s pKa, the molecule is fully deprotonated – anionic

 Be able to recognize titration curves of amino acids

o When an amino acid is titrated, the curve represents the reaction of each functional group with hydrogren ions.
 When titrated, alanine behaves like a diprotic acid b/c it has 2 titratable groups in its alpha-carboxyl and
alpha-amine
 PI: the midpoint of the curve represents the point in which the molecule is electrically neutral
 Histidine titrates as a triprotic acid with 3 pKa values.
 The side chain releases its proton before the alpha amine because the pKa value is lower.
o Therefore, this would be the zwitterionic form of histidine.
o Difference between diprotic and triprotic
 Know how to read and interpret amino acid pKa table
o In free amino acids, the alpha-carboxyl and alpha amino groups are titratable
 Thus, EVERY amino acid has 2 ionizable groups.
 Most amino acids are nonionizable – their side chains remain uncharged at ANY pH
o Every amino acid has pKa values associated with the alpha-carboxyl and alpha-amino groups
 The variations in pKa values across amino acids are according to the nature of the side chain.
o The 3rd type of ionizable group exists on the side chain: 7 amino acids inlcude asp, glu, his, cys, tyr, lys, arg
 Know how pH relates to pK of ionizable groups on proteins
o Know how to predict overall charge on peptide at given pH (number of + and – charges): page 94
o Know what the pI is and its significance
 Isoelectric pH (pI) – pH at which a molecule has no net charge i.e. its electrically neutral
 “Iso” = same; molecule has the same number of (+) and (-) charges
o Thus its neutral in overall charge.
 For most “free” amino acids which lack an ionizable side chain, the pI is easily calculated as the
midpoint between the pKa of the alpha amine and alpha carboxyl
o Be able to calculate pI for free amino acids
pK a1 + pK a2
pI =
 2
 For glycine; if the pH of the solution is equal to 5.97, then all the glycine molecules are in the zwitterionic
form.
1
pI = (pK aa - COOH + pK aa - NH 3+ )
2
1
= (2.34 + 9.60) = 5.97
2
Review Exercises Recommended: 7, 8, 9, 10, 12, 15, 17, 20, 22
The Peptide Bond
 The polymerization of amino acids to form a polypeptide chain involves the condensation of a carboxylate (COOH) of one
amino acid with the amino group of another amino acid.
o A condensation reaction: water molecule is eliminated. The resulting amide bond linked the two amino acids is a
peptide bond.
3
 Ch 3: Amino Acids and Peptides
 Peptide bond – amide bond between two amino acids in protein; its actually an amide functional group.
o It’s a covalent bond formed between alpha-COOH of one amino acid + the alpha-NH2 of another.
 Peptides – a molecule formed by linking a minimum of two to a few dozen amino acids, connected by
amide/peptide bonds.
 Any molecule containing more than a few dozen residues is considered a protein.
o Polypeptide chain – formed by linking the component amino acids via peptide/amide bonds
 It is the backbone of a protein, with the R group pointing out from the backbone.

 The residue with a free amino group is on the left (N-terminus) and the residue with the free carboxylate is
on the right (C-terminus).
 Except for the two terminal groups, the charged amino and carboxylate of each amino acid are eliminated
in forming the peptide bonds.
 The electrostatic properties of the polypeptide therefore depend primarily on the identities of the
side chain that project out from the polypeptide backbone.
 Carbon-nitrogen bond in a peptide bond is usually written as a single bond.
o BUT since the carbon is double bonded to an oxygen and the adjacent nitrogen holds a lone pair, resonance exists.
 Resonance – structural formulas that differ only in position of electrons.
o Peptide bond is a hybrid of two structures –


 The peptide bond is partially double bonded, which has a shorter bond length, translating into a stronger
bond than single bonds.
 It is strong enough to prevent free rotation within the bond (sp2).
 Other covalent bonds in peptides
o Oxytocin and vasopressin each carry cyclic cysteine residues that can be oxidized to form joint disulfide bond.
 Hold physiological importance as hormones.
 Know the formation and structure of peptide bonds
o Dehydration of carboxy and amine groups
o Side chains in trans conformation
o Know that a peptide bond has resonance and the significance of this
 Shorter bond length
 Very stable
 No free rotation about C-N bond
 Atoms are very polar and tend to form H-bonds
 Be able to recognize a disulfide bond
o Another type of covalent bond in peptides; results in cyclic structure
Review Exercises Recommended: 27, 35, 39, 40, 49