Peptides and proteins — Biomolecules

Joining amino acids into a chain uses one reaction you already know — amide formation — and then the interesting part begins, because the resulting chain folds, and what it folds into is what it does.

The peptide bond is an amide, and it behaves like one

The carboxyl of one amino acid and the amino group of the next condense, losing water, to give an amide. In this context it is called a peptide bond, but nothing about it is chemically special: it is the same linkage as any amide, with the same consequences.

The most important of those consequences is resonance. The nitrogen lone pair delocalizes into the carbonyl, which gives the C–N bond substantial double-bond character and three results that matter:

The bond cannot rotate freely, so the six atoms of the peptide unit are held roughly planar.
The nitrogen is not basic in the way an amine is — its lone pair is tied up in the delocalization.
Amides are the least reactive acyl derivative, which is exactly why proteins do not spontaneously hydrolyze. That is the same reactivity ladder from the Carboxylic Acids chapter, and here it is doing biological work.

Peptides are written and numbered from the N-terminus (the free amino end) to the C-terminus (the free carboxyl end). The convention is universal, so "Gly-Ala" and "Ala-Gly" are different compounds — the order is a structural statement, not a list.

Four levels of structure

The second resonance structure of an amide, and what follows from it. Pushing the nitrogen lone pair into the carbonyl gives the C–N bond partial double-bond character, and planarity, low basicity and low reactivity all fall out of that one move.The basicity consequence is the one that inverts against intuition. A lone pair on nitrogen looks like a base, and here it is the reason the nitrogen is not one — delocalization makes a lone pair less available, not more.

Primary — the sequence of amino acids, held together by covalent peptide bonds. This is the only level fixed by covalent chemistry alone.
Secondary — local, repeating shapes held by hydrogen bonds between backbone N–H and C=O groups. The two standard motifs are the α-helix and the β-sheet. Note that the side chains are not involved; this level is about the backbone.
Tertiary — the whole chain's three-dimensional fold, held by side-chain interactions: hydrophobic packing, hydrogen bonds, salt bridges between acidic and basic side chains, and disulfide bonds between cysteines.
Quaternary — how two or more separate folded chains assemble. Hemoglobin's four subunits are the standard example; not every protein has this level.

The one covalent cross-link in that list is the disulfide bond. Two cysteine thiols are oxidized to an S–S bond, and because it is covalent it survives conditions that unfold everything else — which is why reducing agents that break disulfides are used to denature proteins deliberately.

Why hydrophobic side chains end up inside

A folded protein in water buries its nonpolar side chains in the interior and presents its polar and charged ones to the solvent. The usual shorthand is that nonpolar groups "avoid water", which is close enough to be useful and slightly misleading: the dominant term is what happens to the water, which is forced into a more ordered arrangement around a nonpolar surface. Burying those surfaces releases that water, and the entropy gained is what drives the fold.

The practical version is still the simple one, and it predicts correctly: leucine, valine and phenylalanine inside; aspartate, lysine and serine outside.

Worked example — reading a sequence for structure

A short peptide reads Cys-Leu-Asp-Lys-Val-Cys. What can you say without knowing anything else?

Two cysteines — they can form a disulfide bond, closing the peptide into a loop. That is a covalent constraint on the shape and the first thing to notice.

Asp and Lys — one acidic and one basic side chain, so at physiological pH one is negative and the other positive, and they can form a salt bridge.

Leu and Val — nonpolar, so they will pack against each other or against other hydrophobic regions rather than facing the solvent.

None of this requires knowing what the peptide does. Reading a sequence for the kinds of side chain present is most of what a question at this level is asking for.

Hydrolysis, and how sequences are determined

Heating a protein in strong aqueous acid hydrolyzes every peptide bond and returns the mixture of free amino acids — the amide hydrolysis from the Carboxylic Acids chapter, run to completion. Those conditions are harsh enough to cost you tryptophan and to turn asparagine and glutamine into aspartic and glutamic acid, so the result is the composition with a known correction applied. It tells you the composition but destroys the sequence, which is why sequencing uses selective methods that remove one residue at a time from an end instead.

What carries forward

Everything structural here rests on two facts from earlier chapters: an amide is resonance-stabilized and therefore planar and unreactive, and hydrogen bonds are weak individually and decisive in bulk. The biology is an application of both rather than a new set of rules.