This discussion, prepared for the Protein Society's symposium honoring
the 100th anniversary of Kaj Linderstrom-Lang, shows how hydrogen exc
hange approaches initially conceived and implemented by Lang and his c
olleagues some 50 years ago are contributing to current progress in st
ructural biology. Examples are chosen from the active protein folding
field. Hydrogen exchange methods now make it possible to define the st
ructure of protein folding intermediates in various contexts: as tenuo
us 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 cons
iders the rise of these capabilities from their inception at the Carls
berg Labs to their contemporary role as a significant tool of modem st
ructural biology.