How fast are the motions of tertiary-structure elements in proteins?

TL;DR

This paper reviews recent experimental techniques and studies that reveal protein tertiary-structure elements, such as domains, can undergo ultrafast motions on nanosecond to microsecond scales, often faster than the proteins' functional cycles.

Contribution

It introduces recent experimental evidence of ultrafast domain motions in proteins and discusses their potential functional roles, highlighting motions faster than previously thought.

Findings

Ultrafast domain motions observed in proteins.

Fast motions may optimize substrate interactions.

Motions can be faster than functional cycles.

Abstract

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.