1.6 Proteins

R groups supply the chemical diversity needed for protein folding and function. Some are non-polar, some polar but uncharged, some acidic and negatively charged, and some basic and positively charged under cellular conditions.

A change in one amino acid can have little effect if it is chemically conservative and surface-exposed, or a major effect if it disrupts an active site, hydrophobic core, subunit interface or essential bond. Primary structure therefore constrains every higher level of protein organization.

Primary structure is the number and linear sequence of amino acids in a polypeptide. Peptide bonds form the covalent backbone. Primary structure is not merely the first temporary stage: it remains present in the completed protein and constrains every later interaction. Because genes determine amino-acid sequence through codons, information in DNA becomes chemical pattern in a polypeptide.

Secondary structure is regular local folding stabilized mainly by hydrogen bonds between backbone carbonyl oxygen and amide hydrogen atoms. In an α helix the backbone coils and hydrogen bonds form between turns. In a β pleated sheet, extended segments lie beside one another and hydrogen-bond across the sheet. One polypeptide may contain helices, sheets and less regular connecting regions.

The hydrogen bonds of secondary structure involve backbone groups, not a special repeating sequence of R groups. However, side-chain size and chemistry influence which conformations are possible. Keratin contains extensive α-helical regions suited to fibrous assemblies, while silk fibroin contains β-sheet-rich regions whose aligned chains create strength. Structure labels identify levels of organization; they should not be mistaken for separate molecules.

Tertiary structure is the overall three-dimensional conformation of one polypeptide. In an aqueous environment, non-polar side chains tend to cluster away from water in the protein interior, while many polar and charged side chains remain exposed. This hydrophobic effect is a major driver of folding. It is not an attraction between hydrophobic groups so much as a consequence of water becoming less constrained when non-polar surfaces cluster.

Several interactions stabilize the fold. Hydrogen bonds form among polar groups; oppositely charged R groups form ionic interactions; temporary dipoles contribute van der Waals attractions at close range. Two cysteine side chains can be oxidized to form a covalent disulfide bridge. Disulfide bonds are stronger than the non-covalent interactions and are especially valuable in extracellular proteins exposed to changing conditions.

The distribution of polar and non-polar amino acids depends on location. A soluble globular protein often presents hydrophilic groups to water and hides hydrophobic groups. In an integral membrane protein, residues contacting phospholipid tails are largely non-polar, whereas a channel pore that transports ions is lined by hydrophilic residues. Enzyme active sites position side chains whose shapes, charges and polarity complement the substrate and transition state.

Quaternary structure occurs when two or more polypeptide subunits associate into one functional protein. The same interaction types that stabilize tertiary structure can stabilize subunit interfaces. Not every protein has quaternary structure: a functional single polypeptide may have only primary, secondary and tertiary levels. Counting polypeptide chains, rather than the number of helices or domains, determines whether quaternary structure is present.

Hemoglobin contains four globin subunits. Each carries a heme prosthetic group with an iron ion that can bind oxygen reversibly. Subunit association allows cooperative behavior: binding oxygen to one subunit alters the quaternary conformation and increases the affinity of others. This helps hemoglobin load oxygen where partial pressure is high and unload it in respiring tissues. The behavior cannot be explained by the heme iron alone; it emerges from heme, tertiary structure and subunit interaction.

Other quaternary proteins illustrate how subunit number and arrangement support function. Antibodies contain two heavy and two light chains joined partly by disulfide bonds, producing two antigen-binding regions. Collagen contains three polypeptide chains wound into a rope-like triple helix. Myosin contains multiple chains organized into motor heads and a long tail. A subunit is a polypeptide component, not necessarily a separate functional protein.

Globular proteins fold into compact shapes and commonly perform dynamic functions. Enzymes catalyse reactions; antibodies recognize antigens; insulin acts as a hormone; myoglobin binds oxygen in muscle. Many globular proteins are soluble because hydrophilic groups cover much of their surface, although membrane globular domains and hydrophobic binding pockets are important exceptions. Their precise tertiary or quaternary shapes create active sites and binding surfaces.

Fibrous proteins are elongated and usually have structural roles. Repetitive sequences and extensive secondary structure permit parallel assembly and cross-linking. Collagen fibrils provide tensile strength in tendons, ligaments, skin and other connective tissues. Keratin contributes to hair, nails and epidermal structures. Fibrous proteins are commonly insoluble, which helps them remain in place, but 'fibrous' refers primarily to morphology and mechanical role rather than one universal bond pattern.

Structure–function explanations should be specific. Collagen's three-chain organization and covalent cross-links resist pulling forces. Antibody variable regions create complementary binding surfaces. DNA helicase subunits form a ring-shaped motor around nucleic acid. Insulin's chains and disulfide bonds preserve a receptor-binding conformation. Saying only that a protein has a 'special shape' is not enough; identify the feature and what interaction or mechanical property it enables.

A conjugated protein contains a permanently associated non-protein component called a prosthetic group. Hemoglobin and myoglobin contain heme; some enzymes contain metal ions or organic cofactors. The prosthetic group can supply chemical abilities unavailable from amino-acid side chains alone. Heme iron binds oxygen and participates in electron transfer in different proteins, while the surrounding polypeptide tunes its reactivity and prevents uncontrolled chemistry.

A protein without a prosthetic group is non-conjugated; collagen and insulin are examples. This classification is independent of globular versus fibrous and independent of quaternary structure. Hemoglobin is globular, conjugated and quaternary; collagen is fibrous, non-conjugated and quaternary. Multiple classification axes can describe the same protein because each answers a different structural question.

The proteome is the complete set of proteins expressed by a cell, tissue or organism at a particular time. Unlike a genome, it changes with cell type and conditions because genes are expressed selectively and proteins are modified and degraded. International protein databases allow researchers to compare sequences, structures, modifications and amino-acid frequencies across species. Conserved similarities can support hypotheses about shared ancestry and function, while discrepancies prompt investigation rather than being discarded.

Protein synthesis does not always end when a ribosome releases the chain. Initial amino acids may be removed, specific residues can be phosphorylated or glycosylated, and polypeptides may be cleaved into an active form. Insulin is processed from a longer precursor, while many secreted proteins acquire carbohydrate groups in the endomembrane system. These modifications expand functional diversity beyond the twenty genetically encoded side chains.

Molecular chaperones help other proteins fold by shielding exposed hydrophobic regions and reducing inappropriate aggregation. They do not specify a different final sequence or become part of every finished protein. Their importance is greatest when newly synthesized chains emerge in a crowded cytoplasm or when heat and other stress increase the chance of misfolding.

Comparing collagen and hemoglobin reveals why broad protein labels need structural detail. Collagen's repeated sequence permits three chains to pack tightly, and covalent cross-links transfer tension between molecules. Hemoglobin's compact subunits preserve soluble surfaces and movable interfaces. Both have quaternary structure, but one is optimized for mechanical continuity and the other for reversible, cooperative ligand binding.