Abstract
The prevailing current view of protein folding is the thermodynamic hypothesis, under which the native folded conformation of a protein corresponds to the global minimum of Gibbs free energy G. We question this concept and show that the empirical evidence behind the thermodynamic hypothesis of folding is far from strong. Furthermore, physical theory-based approaches to the prediction of protein folds and their folding pathways so far have invariably failed except for some very small proteins, despite decades of intensive theory development and the enormous increase of computer power. The recent spectacular successes in protein structure prediction owe to evolutionary modeling of amino acid sequence substitutions enhanced by deep learning methods, but even these breakthroughs provide no information on the protein folding mechanisms and pathways. We discuss an alternative view of protein folding, under which the native state of most proteins does not occupy the global free energy minimum, but rather, a local minimum on a fluctuating free energy landscape. We further argue that ΔG of folding is likely to be positive for the majority of proteins, which therefore fold into their native conformations only through interactions with the energy-dependent molecular machinery of living cells, in particular, the translation system and chaperones. Accordingly, protein folding should be modeled as it occurs in vivo, that is, as a non-equilibrium, active, energy-dependent process.
Highlights
For the last six decades, the general understanding in the protein folding field has been that proteins fold into their native conformations driven by decrease in Gibbs free energy
The cornerstone assumption in the field of protein folding is that proteins spontaneously fold into their native conformations driven by negative ∆G
It is generally assumed that the native conformation of a protein is the global minimum of Gibbs free energy
Summary
For the last six decades, the general understanding in the protein folding field has been that proteins fold into their native conformations driven by decrease in Gibbs free energy (negative ∆G). Energy landscape likely applies only folding of small, thermodynamically stable proteins (b) Folding energy landscape for a protein that folds in vivo is poorly understood, but most likely, as it occurs spontaneously, in vitro, in isolation from all cellular compounds. (d) Native conformations proteins are protein likely to as occupy thermodynamic minima different (c) Folding energy landscapeof ofmost the same small in (a)local is most likely substantially with higher Gibbs free energy than their unfolded conformations (positive ΔG of folding). Such and far more complex when folding occurs in a crowded cellular environment. Such native conformation can only arise as a result of active, energy dependent folding process
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