The Helix He Folded in Bed With the Flu

The Mechanism

Linus Carl Pauling was born in Portland, Oregon, on February 28, 1901, the son of a struggling drugstore proprietor who died when Pauling was nine. He took his bachelor's degree in chemical engineering at Oregon Agricultural College in 1922, his PhD in physical chemistry at Caltech in 1925, and then spent two years on a Guggenheim Fellowship at Munich, Copenhagen, and Zurich learning the new quantum mechanics from Sommerfeld, Bohr, and Schrödinger directly. He joined the Caltech faculty in 1927, became full professor in 1931, and over the following decade applied the new quantum mechanics to chemistry — most importantly in his 1939 book *The Nature of the Chemical Bond*, in which he formulated the principles of *resonance* and *electronegativity* and showed that the molecular geometry of every compound in chemistry could be predicted from quantum-mechanical principles applied to its constituent bonds. By the late 1930s, Pauling had begun applying these principles to *proteins* — the large biological molecules whose three-dimensional folding had been an unsolved problem since the work of the German chemist Emil Fischer in the 1890s. Proteins are polymers of *amino acids*, joined head-to-tail by *peptide bonds*. The peptide bond — the C-N bond between adjacent amino acids — has, Pauling showed in 1937, a *partial double-bond character* due to resonance, which forces the six atoms on either side of the bond (the carbonyl C, the carbonyl O, the amide N, the amide H, and the two flanking α-carbons) to lie in a single plane. The protein backbone, therefore, consists of a series of rigid planar units joined by single bonds (the N-Cα and Cα-C bonds) about which rotation is permitted. The geometry of any folded protein, Pauling reasoned, must be the geometry that maximizes hydrogen bonding between the amide N-H and the carbonyl C=O groups of the rigid peptide planes — subject to the constraint that the rotations about the N-Cα and Cα-C bonds keep all the planar units in physically allowed positions. Through 1937-1939, Pauling and Robert Corey (his crystallographer collaborator at Caltech) examined every plausible regular helical arrangement of the polypeptide chain, looking for the one that satisfied all these constraints simultaneously. They could not find one. The reason — Pauling realized only later, in 1948 — was that they had been making the same hidden assumption as every other crystallographer of the period: that the helix must repeat after a *whole number* of residues per turn, because that was the assumption that fit the available X-ray diffraction data on synthetic polypeptides. The constraint was false. The actual helix did not repeat after a whole number. By Easter weekend of 1948, Pauling was a visiting professor at Oxford for the spring term. He came down with a cold and went to bed for several days. Bored, he took to his bedside table a sheet of paper and a pencil. He drew a polypeptide chain to roughly correct scale, with each peptide unit marked as a rigid rectangle. He folded the strip into a helix, *insisting* on keeping every peptide bond planar, *insisting* on maximizing the hydrogen bonds — and *not* insisting on a whole-number repeat. The first plausible helix he found had 3.6 residues per turn (the rise per residue was 1.5 Å; the pitch per turn was 5.4 Å) and a hydrogen bond between the N-H of each residue and the C=O of the *fourth* residue along the chain. The hydrogen bonds were of correct length (2.79 Å) and correct geometry. The full revelation came when he realized that this helix — and a similar but tighter *3.0₁₀* variant with 3.0 residues per turn — satisfied every constraint he had been imposing for ten years. He returned to Caltech in the fall of 1948, recruited Robert Corey and the postdoctoral fellow Herman Branson, and built physical scale models with metal rods and balls to confirm the geometry. The full theoretical paper — Pauling, L., Corey, R.B. & Branson, H.R., "The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain," *PNAS* 37(4): 205-211 (April 1951) — appeared in May 1951 as the lead paper in a series of *seven consecutive papers* in the same issue of *Proceedings of the National Academy of Sciences*, all on the structures of proteins. The papers between them announced the alpha helix (the 3.6 residue/turn helix Pauling had folded in Oxford), the beta sheet (a parallel-strand structure that explains the structure of silk), and the polyproline II helix (the structure of collagen). The alpha helix is the most common structural element in every protein in every living organism: about 30% of all residues in all known protein structures are in alpha-helical conformation. The beta sheet accounts for another 23%. Between them, the two structural elements proposed in those seven 1951 papers describe more than half of the secondary structure of every protein ever sequenced. Two years later, in February 1953, Pauling and Corey published — also in *PNAS* — a proposed structure for DNA, a *triple-helix* with phosphates on the inside. The structure was wrong. Pauling, in California, did not have access to the highest-quality X-ray photographs of DNA, which were in the Cavendish-Royal Holloway King's College laboratory in London. The correct structure — a double-helix with phosphates on the outside, the bases paired through the middle — was published by James Watson and Francis Crick in *Nature* two months later, in April 1953. Watson and Crick had used, without attribution, Rosalind Franklin's now-famous Photograph 51 (an X-ray diffraction image of B-form DNA), which they had been shown by Franklin's colleague Maurice Wilkins. The alpha helix, by contrast, was Pauling's alone — derived from chemistry first principles, in bed, with a strip of paper. He won the 1954 Nobel Prize in Chemistry "for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances," with the alpha helix as the central application. He won the 1962 Nobel Peace Prize for his decade-long campaign against atmospheric nuclear weapons testing, becoming the only person in history to win two unshared Nobels. He died on August 19, 1994, in Big Sur, California, age 93. The strip of folded paper from the Oxford bedside table is preserved in the Linus Pauling Papers at Oregon State University, in a small archival folder labeled *Original Alpha-Helix Construction*.