Abstract
“How do proteins fold?” Researchers have been studying different aspects of this question for more than 50 years. The most conceptual aspect of the problem is how protein can find the global free energy minimum in a biologically reasonable time, without exhaustive enumeration of all possible conformations, the so-called “Levinthal’s paradox.” Less conceptual but still critical are aspects about factors defining folding times of particular proteins and about perspectives of machine learning for their prediction. We will discuss in this review the key ideas and discoveries leading to the current understanding of folding kinetics, including the solution of Levinthal’s paradox, as well as the current state of the art in the prediction of protein folding times.
Highlights
The problem of protein folding is one of the most important problems of modern theoretical biophysics. It appeared more than 50 years ago when Anfinsen et al demonstrated that proteins can spontaneously fold into their unique 3D native structure in vitro [1,2]
We will review the history of investigation and solution of the conceptually major and the most puzzling question: How can proteins confidently find their unique 3D native structure among zillion alternatives in a biologically reasonable time? We will leave aside the other problems, such as prediction of protein 3D native structure from protein sequence, which has an applied character and is still unsolved in a general case [3], despite the substantial recent progress based on usage of the multiple deep neural networks, see [4,5]
The “all-or-none” transition means that a sufficiently high free-energy barrier separates the native and denatured states. It is the height of this barrier that defines the kinetics of protein folding and unfolding
Summary
The problem of protein folding is one of the most important problems of modern theoretical biophysics. Some further examples of this are summarized in the review [6] It seems that there is no fundamental difference between the in vivo (co-translational) folding and in vitro refolding of denatured proteins, at least not for small, single-domain globular proteins: In both cases, three-dimensional native protein structures emerge only after the entire sequence is available. The “all-or-none” transition means that a sufficiently high free-energy barrier separates the native and denatured states It is the height of this barrier that defines the kinetics of protein folding and unfolding. Just the barrier height is to be estimated to elucidate the Levinthal’s paradox
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