  Protein motions occur on multiple time and distance scales. Large-scale
motions of protein tertiary-structure elements, i.e. domains, are particularly
intriguing as they are essential for the catalytic activity of many enzymes and
for the functional cycles of protein machines and motors. Theoretical estimates
suggest that domain motions should be very fast, occurring on the nanosecond or
microsecond time scales. Indeed, free-energy barriers for domain motions are
likely to involve salt bridges, which can break in microseconds. Experimental
methods that can directly probe domain motions on fast time scales have
appeared only in recent years. This Perspective discusses briefly some of these
techniques, including NMR and single-molecule fluorescence spectroscopies. We
introduce a few recent studies that demonstrate ultrafast domain motions, and
discuss their potential roles. Particularly surprising is the observation of
tertiary-structure element dynamics that are much faster than the functional
cycles in some protein machines. These swift motions can be rationalized on a
case-by-case basis. For example, fast domain closure in multi-substrate enzymes
may be utilized to optimize relative substrate orientation. Whether a large
mismatch in time scales of conformational dynamics vs. functional cycles is a
general design principle in proteins remains to be determined.
