PubMed · 8913696
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1996. Biophysical methods.. https://doi.org/10.1016/s0959-440x(96)80041-8
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The Carlsberg Laboratory in Copenhagen has had a long tradition of outstanding science. At the time covered by this discussion, Kjeldahl, Sørensen, and Linderstrøm-Lang had been consecutive directors of the Chemical Laboratory for 83 years. Lang's inspired leadership began in the 1930s with a number of innovations (study of metabolism in single cells, titrations in non-aqueous solvents, relation of proteolysis to structure) but it was not until the early 1950s that Denmark had sufficiently recovered from the war for the laboratory to enter world science again. During World War II, Lang had been active in the Danish resistance movement. After the war, a number of major advances were being made that would revolutionize the field of protein chemistry (Pauling and Corey's H-bonded structures, Sanger's sequencing techniques, chromatography, Watson and Crick structures, modern instrumentation). The time for the new field of the physical biochemistry of proteins had arrived. Lang, with his broad experience, adventurous spirit, and genius for innovation, created an environment that was ideal for the convergence of these disconnected advances into a uniform science. The emphasis was to be on quantitative measurements on proteins in solution with interpretations based on molecular structures. During an all-too-brief period of time, Lang's laboratory attracted a large fraction of those who were destined to be the leaders of the next generation of protein chemists. At this time, the Carlsberg Laboratory was probably the most scientifically exciting environment for a protein chemist. The methods developed at that time-hydrogen exchange, limited proteolysis, optical rotatory dispersion, volume changes accompanying protein reactions, automatic titrations-are still all in common use and many of the visitors to the laboratory in that period and their students are still playing major roles in protein research. Lang's other qualities should not be ignored. He was not only a great scientist but also a musician, raconteur, artist, and an exceptionally warm and compassionate human being.
This discussion, prepared for the Protein Society's symposium honoring the 100th anniversary of Kaj Linderstrøm-Lang, shows how hydrogen exchange approaches initially conceived and implemented by Lang and his colleagues some 50 years ago are contributing to current progress in structural biology. Examples are chosen from the active protein folding field. Hydrogen exchange methods now make it possible to define the structure of protein folding intermediates in various contexts: as tenuous molten globule forms at equilibrium under destabilizing conditions, in kinetic intermediates that exist for less than one second, and as infinitesimally populated excited state forms under native conditions. More generally, similar methods now find broad application in studies of protein structure, energetics, and interactions. This article considers the rise of these capabilities from their inception at the Carlsberg Labs to their contemporary role as a significant tool of modern structural biology.