Nature’s Shortcut to Protein Folding

Abstract

This Feature Article presents a view of the protein folding transition based on the hypothesis that Nature has built features within the sequences that enable a Shortcut to efficient folding. Nature’s Shortcut is proposed to be the early establishment of a set of nonlocal weak contacts, constituting protein loops that significantly constrain regions of the collapsed disordered protein into a native-like low-resolution fluctuating topology of major sections of the backbone. Nature’s establishment of this scaffold of nonlocal contacts is claimed to bypass what would otherwise be a nearly hopeless unaided search for the final three-dimensional structure in proteins longer than ∼100 amino acids. To support this main contention of the Feature Article, the loop hypothesis (LH) description of early folding events is experimentally tested with time-resolved Förster resonance energy transfer techniques for adenylate kinase, and the data are shown to be consistent with theoretical predictions from the sequential collapse model (SCM). The experimentally based LH and the theoretically founded SCM are argued to provide a unified picture of the role of nonlocal contacts as constituting Nature’s Shortcut to protein folding. Importantly, the SCM is shown to reliably predict key nonlocal contacts utilizing only primary sequence information. This view on Nature’s Shortcut is open to the protein community for further detailed assessment, including its practical consequences, by suitable application of advanced experimental and computational techniques.

Successes and challenges in simulating the folding of large proteins

“…This nonlocal loop formation would encourage the formation of local structure, such as foldons (123,124). Application of the sequential collapse-based method to AKE agreed with the results of timeresolved FRET experiments (122) and the previous SBM folding simulations.…”

“…The smaller domains transiently folded and unfolded, stabilizing only upon folding of the larger discontinuous domain, whose folding constrained the termini of the smaller domains into near-native conformations and reduced the entropic cost of folding these domains. Similar entropic considerations go into the physics-based sequential collapse model in which the closure of loops with lengths on the order of 65 amino acids, too large to crowd the side chains and too small to have very large entropic penalties, are postulated to be one of the earliest events in protein folding (122). This nonlocal loop formation would encourage the formation of local structure, such as foldons (123,124).…”

Interdiction of Protein Folding for Therapeutic Drug Development in SARS CoV-2

“… 7 , 12 , 13 The earliest folding initiation event in both cases will be predicted employing the sequential collapse model (SCM). 14 , 15 In the SCM, the multistate folding process of proteins longer than ∼100 amino acids is initiated by formation of specific nonlocal contacts called primary contacts. These primary contacts help constrain the folding process by dividing the protein into several smaller domains.…”

The Molten Globule, and Two-State vs. Non-Two-State Folding of Globular Proteins

“…In the interim, there have been many experimental studies on protein folding (refs. [2][3][4] and references cited therein). From these studies, it is now clear that there are two types of folding behavior, i.e., non-two-state folding, involving at least one folding intermediate, and two-state folding without any detectable intermediate during kinetic refolding from the fully unfolded (U) state to the native (N) state [5,6].…”