Part 2: Protein structure, enzymes and inhibition

Connect primary sequence to three-dimensional structure and explain stereospecific binding at an enzyme active site.

Primary, secondary and tertiary describe different features

Do not define primary structure as simply “a straight chain”; it is the residue sequence. A molecule may contain several secondary-structure regions connected by other segments. The tertiary shape positions functional groups in space and therefore matters to binding and catalysis.

Backbone hydrogen bonds organise helices and sheets

An α-helix is held by hydrogen bonds between backbone carbonyl oxygen and N–H hydrogen further along the chain. In β sheets, extended backbone segments lie side by side with hydrogen bonds between them; the segments can belong to one folded chain or different chains.

Draw O lone pair···H–N with a near-linear arrangement at H, and keep the N–H bond covalent. The peptide C–N bond is not the hydrogen bond. Different side chains can also form hydrogen bonds in tertiary structure, but that does not replace the backbone explanation of α helices and β sheets.

A disulfide bridge is a covalent bond

Two cysteine –CH₂SH side chains can be oxidised to a –CH₂–S–S–CH₂– bridge. This covalent link is stronger than an individual hydrogen bond. Oppositely charged side chains, such as COO⁻ and NH₃⁺ under suitable pH conditions, can attract electrostatically. Uncharged polar side chains can hydrogen-bond; non-polar groups tend to cluster away from water.

June 2022 Paper 2 Q04.4–04.5 distinguished disulfide links, hydrogen bonds and ionic interactions, including why an S–S bridge is stronger than an individual H bond. Name the actual side-chain groups, then state the bond/interaction. Changing pH can change group charges and alter folding.

Denaturation changes higher-level structure and can destroy an active-site shape without necessarily hydrolysing the peptide backbone. Strong hydrolysis is a different process that breaks peptide bonds. Not every structural change is automatically reversible.

The active site has both a shape and binding chemistry

The enzymes considered here are protein catalysts. Their folded active site binds a suitable substrate through correctly positioned interactions, producing an enzyme–substrate complex and an alternative pathway with lower activation energy. Products must be released so the site can be reused; the enzyme is not consumed overall.

A chiral active site can distinguish enantiomers. One may place all required functional groups at the right positions to form binding interactions, while its mirror image cannot. This is stereospecificity, not just a statement that one isomer is “bigger”. The lock-and-key model is useful at this level; real proteins can also change conformation during binding.

Temperature and pH can change reaction rate or protein structure. The fact that warming initially speeds collisions does not mean an enzyme will keep becoming faster indefinitely. Avoid confusing a reduced rate with proof that every protein bond has broken.

Blocking binding can reduce catalytic activity

An active-site inhibitor can bind where a substrate would normally bind and reduce the number of sites available for productive substrate binding. A suitable drug may exploit that interaction. Some inhibitors bind elsewhere or act differently, so active-site blocking is the specified example rather than a definition of every inhibitor.

Computer modelling can compare candidate shapes, functional-group positions and interactions with a target site. Predictions guide synthesis and testing; they do not establish efficacy or safety on their own. A related enzyme or receptor elsewhere may also bind the molecule, helping explain unwanted effects.

Quick checks

Original Finesse questions. Reveal the indicative worked solutions after attempting each question; these are not official AQA mark allocations.

Sources