Protein Folding and Misfolding: A Perspective from Theory

Abstract

IntroductionIn appropriate physiological milieu proteins spontaneously fold into their functional three-dimensional structures. The amino acid sequences of functional proteins contain all the information necessary to specify the folds [1,2]. The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu. The wide variety of highly specific structures that result from protein folding and that bring key functional groups into close proximity has enabled living systems to develop astonishing diversity and selectivity in their underlying chemical processes. In addition to generating biological activity, we now know that folding is coupled to many other biological processes, including the trafficking of molecules to specific cellular locations and the regulation of cellular growth and differentiation [3,4].Add to it, correctly folded proteins have long-term stability in crowded biological environments and are able to interact selectively with their natural partners. It is therefore not surprising that the failure of proteins to fold correctly is the origin of a wide variety of pathological conditions [5]. Some concepts, such as energy landscape, Gibbs energy landscape and co-operativity frequently used in the theory of protein folding are examined exactly in one-dimensional systems. It is shown that much of the confusion that exists regarding these, and other concepts arise from the misinterpretation of Anfinsen's thermodynamic hypothesis [6].Moreover, proteins are involved in virtually every biological process and their functions range from catalysis of chemical reactions to maintenance of the electrochemical potential across cell membranes. The molecular conformation of proteins is sensitive to the nature of the aqueous environment [7]. They are synthesized on ribosomes as linear chains of amino acids in a specific order from information encoded within the cellular DNA. To function, it is necessary for these chains to fold into the unique native three dimensional structures that are characteristic for each protein (Figure 1). This involves a complex molecular recognition phenomenon that depends on the cooperative action of many relatively weak non-bonding interactions. As the number of possible conformations for a polypeptide chain is astronomically large, a systematic search for the native (lowest energy) structure would require an almost infinite length of time. Recently, significant progress has been made towards solving this paradox and understanding the mechanism of folding. This has come about through advances in experimental strategies for following the folding reactions of proteins in the laboratory with biophysical techniques, and through progress in theoretical approaches that simulate the folding process with simplified models [8,9].Protein folding is a problem of great importance in both life sciences and biotechnolog...

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“…As newly synthesised proteins are produced, they undergo an 'on-pathway' folding process to the native state, involving condensation of hydrophobic residues into a non-solvent exposed core, while the remaining residues sample available structural conformations. The folding process is largely 'downhill', with successive structures being lower in energy with fewer degrees of freedom, thereby rapidly accelerating the process [1][2][3]. However, conditions of cellular stress can render proteins unable to adopt their native conformation, instead directing proteins towards 'off-pathway' folding mechanisms.…”