New view of protein folding

Lazaridis T. and Karplus M. New view of protein folding reconciled with the old through multiple unfolding simulations. Science (1997) 278(N5345) 1928-1931. 

Recent studies have shown a radically different picture of the unfolded state. In this new view, unfolded proteins have a more limited range of conformations than was formerly appreciated. This provides a basis for understanding not only the nature of the unfolded state but also the earliest events that occur during folding. 

Abstract We discuss recent experiments and theories concerning protein collapse and folding. Experiments using multicomponent solutions have revealed much about the mechanism of folding. Simulation and theory have been used to interpret thermodynamic and fluorescence correlation spectroscopy experimental results. We consider the theoretical arguments using variations of the free energy with respect to fluctuations in number and composition to consider recent experiments. We find new measures of protein stability tendencies offer a different view than the often poorly defined hydrophobic effect. 

The single funnel hypothesis also provides a mechanism for folding. Indeed, if the free energy landscape of proteins has the form of a single funnel, a trajectory driven solely by thermal fluctuations, will always take an unfolded protein, through many possible pathways down the funnel, to the native structure that is located at the bottom. This new view (of many pathways) was later reconciled with Levinthal s old view (of one specific pathway for folding ), by considering that in some cases one pathway may be dominant. ... 

The term "structural genomics" is used to describe how the primary sequence of amino acids in a protein relates to the function of that protein. Currently, the core of structural genomics is protein structure determination, primarily by X-ray crystallography, and the design of computer programs to predict protein fold structures for new proteins based on their amino acid sequences and structural principles derived from those proteins whose 3-dimensional structures have been determined. Plant natural product pathways are a unique source of information for the structural biologist in view of the almost endless catalytic diversity encountered in the various pathway enzymes, but based on a finite number of reaction types. Plants are combinatorial chemists par excellence, and understanding the principles that relate enzyme structure to function will open up unlimited possibilities for the... 

This section has addressed from a theoretical point of view the question of how protein space can be searched efficiently and thoroughly, either in the laboratory or in Nature. It was shown that point mutation alone is incapable of evolving systems with substantially new protein folds. It was further... 

The previous section looked at examples in which detailed analysis of specific proteins identified as targets of the heat shock response has led to the identification of new molecular chaperones as well as an expanded view of the requirements for efficient protein production and folding. In this section we focus on how the use of DNA microarrays has provided a global view of the spectrum of targets of a specific stress response, the unfolded protein response (UPR), which plays a critical... 

In short, with the background of a multi-funnel free energy landscape and of a new kinetic mechanism for folding that can be powered by VES, what is proposed here is a new research direction to look for mechanisms of folding that makes use of the fundamental assumption that the initial protein structure must be well defined and that it is probably a helix. In this view, protein structure is not encoded solely in the amino acid sequence, and in the environment in which folding takes place, as Anfinsen noted, but also, and crucially, in the form of the initial structure and in the folding pathway, as pointed out by Levinthal. The new kinetic mechanism proposed involves breaks of the initial helix at specific sites and describes all a, protein structures as a direct result of these breaks, while all of the other types of structures arise when the specific amino acid sequence makes the all a structures unstable. 

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