Protein folding problem: enigma, paradox, solution

Alexei V Finkelstein; Natalya S Bogatyreva; Dmitry N Ivankov; Sergiy O Garbuzynskiy

doi:10.1007/s12551-022-01000-1

Protein folding problem: enigma, paradox, solution

Biophys Rev. 2022 Oct 11;14(6):1255-1272. doi: 10.1007/s12551-022-01000-1. eCollection 2022 Dec.

Authors

Alexei V Finkelstein^{1

2

3}, Natalya S Bogatyreva¹, Dmitry N Ivankov⁴, Sergiy O Garbuzynskiy¹

Affiliations

¹ Institute of Protein Research of the Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia.
² Biotechnology Department of the Lomonosov Moscow State University, 4 Institutskaya Str, 142290 Pushchino, Moscow Region, Russia.
³ Biology Department of the Lomonosov Moscow State University, 1-12 Leninskie Gory, 119991 Moscow, Russia.
⁴ Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia.

Abstract

The ability of protein chains to spontaneously form their three-dimensional structures is a long-standing mystery in molecular biology. The most conceptual aspect of this mystery is how the protein chain can find its native, "working" spatial structure (which, for not too big protein chains, corresponds to the global free energy minimum) in a biologically reasonable time, without exhaustive enumeration of all possible conformations, which would take billions of years. This is the so-called "Levinthal's paradox." In this review, we discuss the key ideas and discoveries leading to the current understanding of protein folding kinetics, including folding landscapes and funnels, free energy barriers at the folding/unfolding pathways, and the solution of Levinthal's paradox. A special role here is played by the "all-or-none" phase transition occurring at protein folding and unfolding and by the point of thermodynamic (and kinetic) equilibrium between the "native" and the "unfolded" phases of the protein chain (where the theory obtains the simplest form). The modern theory provides an understanding of key features of protein folding and, in good agreement with experiments, it (i) outlines the chain length-dependent range of protein folding times, (ii) predicts the observed maximal size of "foldable" proteins and domains. Besides, it predicts the maximal size of proteins and domains that fold under solely thermodynamic (rather than kinetic) control. Complementarily, a theoretical analysis of the number of possible protein folding patterns, performed at the level of formation and assembly of secondary structures, correctly outlines the upper limit of protein folding times.

Keywords: Folding funnel; Free energy landscape; Levinthal’s paradox; Protein 3D structure; Protein folding; “All-or-none” phase transition.

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Publication types

Review