Snapshots of Protein Folding Problem: Implications of Folding and Misfolding Studies

Abstract

Deciphering the code that determines the three-dimensional structure of proteins and the ability to predict the final folded form of a protein is still elusive to molecular biophysists. In the case of several proteins a similar tertiary structure is not accompanied by any significant sequence similarity. The question now remains whether a code beyond the genetic code that describes the arrangement of the amino acid within a three dimensional protein structure. The available data undoubtedly demonstrates that the redundancy of this code must be tremendous. Several techniques such as nuclear magnetic resonance spectroscopy and laser detection techniques, coupled with fast initiation of the folding reaction, can now probe the folding events in milliseconds or even faster and provide highly relevant information. The thermodynamic analysis of the folding process and of kinetic intermediates opens whole new avenue of understanding. Breaking the protein folding code would enable scientists to look at a gene whose function is unknown and predict the three-dimensional structure of the protein it encodes. This would give them a very good idea of what the gene does. In this review we hope to bring together the information available about protein folding with particular emphasis on folding intermediate(s). Additionally, the practical consequences of the solution of the protein folding problem in medicine and biotechnology are also discussed.

Thermodynamics of ideal proteinogenic homopolymer chains as a function of the energy spectrumE, helical propensity ω and enthalpic energy barrier

“…While the classical view of protein folding assigns biological activity only to a single three-dimensional native structure N, modern views of protein folding embrace the existence of intrinsically disordered proteins with biological activity [9,10]. In spite of the great number of theoretical and computational advances, the precise and exact determination of native structures from first principles is still a matter of open debate [11][12][13].…”

“…It is now well established that structural transitions either to ordered-single structures or to multiple intrinsically disordered structures play a fundamental role in the biological activity of proteins and peptides [11,[26][27][28]. To achieve a quantitative analysis of such structural transitions a great number of computational approaches have been developed.…”