Review
Collective protein dynamics in relation to function

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Abstract

Several techniques for the analysis of the internal motions of proteins are available — separating large collective motions from small, presumably uninteresting motions. Such descriptions are helpful in the characterization of internal motions and provide insight into the energy landscape of proteins. The real challenge, however, is to relate large collective motions to functional properties, such as binding and regulation, or to folding. These issues have been recently addressed in several papers.

Introduction

Collective motions within proteins can be derived from atomic interactions given a single experimental structure, from knowledge of at least two molecular conformations or from an analysis of many conformations, as can be generated by the computer simulation technique of molecular dynamics (MD). The analysis of collective motions can be used to investigate the conformational energy landscape, to improve sampling efficiency and in the refinement of X-ray and NMR data. These aspects have been covered recently in an excellent review by Kitao and Go [1••], and earlier by Hayward and Go [2]. In this review, we concentrate on the application of techniques to derive collective motions in relation to function and folding. Aspects of protein function related to motion include substrate binding and product release, regulation and allosteric behavior, and contractile and motor functions. Collective motions of protein fragments must also be involved in the folding process, but their systematic investigation is still in an early stage.

Section snippets

Computational techniques to determine collective motions

Analysis of collective behavior must be based on knowledge of the structural fluctuations that occur as a result of thermal motion in the protein. Such fluctuations can be obtained in various ways.

Normal mode analysis (NMA) is based on the assumption that, over the range of thermal fluctuations, the conformational energy surface can be characterized by the parabolic approximation at a single energy minimum. This assumption is false at physiological temperatures. It ignores both the effect of

Functional motions

In this section, we review recent applications of NMA and EDA that concentrate on understanding functional motions.

GroEL is a chaperonin of considerable interest because of its role in in vivo protein folding. It is a double-ringed cylinder, each ring comprising seven identical subunits. Interest in its allosteric mechanism and, in particular, in the nature of inter-ring communication has stimulated two recent studies. de Groot et al. [19] have applied the distance fluctuation method CONCOORD

Conclusions and outlook

A lot of effort has gone into describing and characterizing the internal motions of proteins. From a biochemical point of view, the connection to function is a crucial aspect, which is just beginning to be uncovered; the days have passed that a mere description of protein internal motions from MD simulations was considered to be of interest. How functional motions relate to detailed molecular characteristics and amino acid sequences is still to be discovered. A practical bottleneck is the time

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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