A 10-minute read
May 19, 2023 was the 109th anniversary of Max Perutz’s birth. Who was he, and how did he contribute to identifying the first protein using X-rays?
According to the protein database, 200,000 structures of proteins and complexes have been identified over the years. The main techniques for structure determination are X-ray crystallography, cryoEM, and Nuclear Magnetic Resonance, while the latest advancements in artificial intelligence have given us a new tool, AlphaFold. Sixty years after the determination of the first protein structures, myoglobin and hemoglobin, by Max Perutz and John Kendrew (Nobel Prize in Chemistry, 1962), X-ray crystallography remains the main method for structural biologists.
However, what was the history behind the journey to this point? How was the first protein identified using X-rays?
Max Perutz, or the “godfather of molecular biology” as many call him, had a very inspiring life and produced impressive research output.
He started his undergraduate studies in Chemistry at the University of Vienna and then moved to the Cavendish Laboratory of Cambridge University. The person who introduced him to X-ray crystallography was J.D. Bernal. While he had the honor to finish his Ph.D. thesis under the support of Sir Lawrence Bragg, a discussion with F. Haurowitz inspired him to start his research on chymotrypsin and hemoglobin. Sixteen years later, the latter awarded him the Nobel Prize.
For these 16 years, Max Perutz was dealing with the phasing problem. From using Fourier synthesis formulas to creating Patterson maps to adapting the isomorphous replacement method, that was the path that Perutz went through until he solved this problem. Creating the Patterson map was characterized by him as “one of the worst and most tedious jobs that have ever been done in my subject”. Yet, again, he didn’t give up. The solution to the phasing problem was then provided by the advancements in isomorphous replacement. John Kendrew used the adaptations Perutz did to determine the structure of a smaller protein, myoglobin.
This is more or less the known history of Max Perutz's research that led him to the Nobel Prize. But during his life, he accomplished a lot more. Here are some additional interesting facts about him.
1. Max Perutz was Austrian, and his parents wanted to enroll him in a law school. However, he chose to study Chemistry and completed his degree in 1936.
2. Because of war, he could not finish his PhD. Sir Lawrence Bragg encouraged him to apply for a grant, and after he got it, he managed to finish his thesis under Bragg’s supervision.
3. His student, Francis Crick, criticized him publicly, saying that his X-ray crystallography would not bring any fruitful results for structural biology.
4. Max Perutz wrote a book called I Wish I Had Made You Angry. It includes a marvelous selection of his essays on science, scientists, and humanity as it was characterized by Sir Alan R. Fersht.
5. Hemoglobin, a Nobel Prize-winning structure, was published in Nature at 5.5 Å resolution.
6. Max Perutz, together with John Kendrew, received the Chemistry Nobel Prize in 1962. That was also the year that his student F. Crick received the Medicine Nobel Prize, together with J. Watson and M. Wilkins, for the discovery of the molecular structure of DNA.
7. Max's Perutz final research project was on the role of polyglutamine repeats in Huntington's disease. His last two scientific papers were finished just ten minutes before he was admitted to a hospital for emergency surgery.
From the first solved protein structures to the newest developments in structural biology, many years and technological advancements have been seen. In the early 1960s, the structures of myoglobin and hemoglobin were solved at 2 Å and 5.5 Å, respectively. Currently, by pushing the limits of technology with brighter, third- and fourth-generation synchrotron facilities and Free Electron Lasers, we can not only achieve much higher resolution for both soluble and membrane protein structures, but also build the path for new, innovative, and exciting techniques.
More and more often, single-crystal experiments are being supplemented with, or even replaced by, Powder Diffraction experiments and serial crystallography. Room-temperature, in-situ, or time-resolved experiments are only some of the advanced dynamic experiments that are gaining more exposure as they provide us with insights into protein mechanisms, interactions, and functions. These advancements, together with better, faster, noise-free detectors, indicate a very bright future!
There are still many proteins to be explored. With the rapid evolution of technology, the right question seems to be not if we can discover them, but when.
DeepMind - AlphaFold
Nobel Prize lecture: “X-ray analysis of hemoglobin”, Max F. Perutz, 1962
Perspective: Cracking the Phase Problem
Structure Of Hemoglobin: A Three-Dimensional Fourier Synthesis of Reduced Human Hemoglobin at 5.5 Å Resolution
A Three-Dimensional Model of the Myoglobin Molecule, Obtained by X-Ray Analysis
Life of Max Perutz (1914-2002)
Max Perutz 1914-2002: 'The godfather of molecular biology'
Fersht, A. Max Ferdinand Perutz OM FRS. Nat Struct Mol Biol 9, 245–246 (2002)