In 1838 the Dutch chemist Gerardus Mulder coined the word protein (from Greek prōteios, "of first importance") for a class of nitrogen-rich substances he believed shared a common composition. He was wrong about the composition but right about the importance: proteins are the molecular machines life is built from — catalyzing every biochemical reaction as enzymes, providing structural support (collagen, keratin, actin), transmitting signals (hormones, receptors), recognizing foreign substances (antibodies), transporting cargo (hemoglobin, kinesins), generating motion (myosin), and reading, copying, and repairing the genome. For most of the twentieth century, predicting a protein's three-dimensional structure from its amino-acid sequence — the protein folding problem — was considered one of biology's deepest unsolved challenges. In 2020, DeepMind's AlphaFold 2 largely solved it.
Proteins are linear polymers of amino acids — twenty standard ones in nearly all life — joined by peptide bonds, with primary structure the linear sequence, secondary structure the local patterns (α-helices and β-sheets stabilized by hydrogen bonds), tertiary structure the full three-dimensional fold of a chain, and quaternary structure the assembly of multiple chains. Folding is driven by hydrophobic interactions (water-fearing residues collapse inward), constrained by hydrogen bonding, fine-tuned by van der Waals contacts, salt bridges, and disulfide bonds. The Anfinsen experiment (1961) showed folding is encoded in the sequence; prediction was hard because the conformational space is astronomical (a 100-residue protein has ~10⁶⁰ possible conformations) and folding is cooperative. Enzymes accelerate biochemical reactions by factors of 10⁶ to 10²³ by binding the substrate in an active site with complementary geometry and electrostatics and stabilizing the transition state, with Michaelis-Menten kinetics (1913) giving the rate as V = V_max × [S] / (K_m + [S]). Allostery regulates many enzymes through binding sites distinct from the active site; cofactors (metals, NAD+, ATP) extend the chemistry beyond what twenty amino acids alone can do; post-translational modifications (phosphorylation, methylation, acetylation, glycosylation, ubiquitination) expand the functional repertoire further — a single gene can produce dozens of distinct functional states. Misfolding causes disease: Alzheimer's (amyloid-β plaques and tau tangles), Parkinson's (α-synuclein), Huntington's (mutant huntingtin), and prion diseases are all protein-aggregation diseases. Protein quality control — chaperones assisting folding, the proteasome degrading damaged proteins, autophagy disposing of larger aggregates — is one of the cell's most elaborate maintenance systems.
AlphaFold 2 (DeepMind, 2021) achieved near-experimental accuracy on the protein-structure-prediction problem that had resisted progress for fifty years, using neural networks trained on the Protein Data Bank plus evolutionary information from multiple sequence alignments to predict structures from sequence in minutes with ~1 Å median RMSD. The AlphaFold Protein Structure Database (2022) released 200 million predicted structures, and AlphaFold 3 (2024) extended prediction to protein-ligand complexes, protein-DNA interactions, and post-translationally modified proteins. The 2024 Nobel Prize in Chemistry went to Demis Hassabis and John Jumper (for AlphaFold) and David Baker (for de novo protein design via RFdiffusion). Therapeutic proteins (monoclonal antibodies, replacement enzymes, GLP-1 agonists, mRNA-encoded antigens) are the fastest-growing class in pharmaceuticals.