Abstract
Extensive experimental and theoretical studies have advanced our understanding of the mechanisms of folding and binding of globular proteins, and coupled folding and binding of intrinsically disordered proteins (IDPs). The forces responsible for conformational changes and binding are common in both proteins; however, these mechanisms have been separately discussed. Here, we attempt to integrate the mechanisms of coupled folding and binding of IDPs, folding of small and multi-subdomain proteins, folding of multimeric proteins, and ligand binding of globular proteins in terms of conformational selection and induced-fit mechanisms as well as the nucleation–condensation mechanism that is intermediate between them. Accumulating evidence has shown that both the rate of conformational change and apparent rate of binding between interacting elements can determine reaction mechanisms. Coupled folding and binding of IDPs occurs mainly by induced-fit because of the slow folding in the free form, while ligand binding of globular proteins occurs mainly by conformational selection because of rapid conformational change. Protein folding can be regarded as the binding of intramolecular segments accompanied by secondary structure formation. Multi-subdomain proteins fold mainly by the induced-fit (hydrophobic collapse) mechanism, as the connection of interacting segments enhances the binding (compaction) rate. Fewer hydrophobic residues in small proteins reduce the intramolecular binding rate, resulting in the nucleation–condensation mechanism. Thus, the folding and binding of globular proteins and IDPs obey the same general principle, suggesting that the coarse-grained, statistical mechanical model of protein folding is promising for a unified theoretical description of all mechanisms.
Highlights
Elucidation of the mechanisms of protein folding and function remains an outstanding challenge in biophysics
We describe conformational selection and induced-fit mechanisms and discuss mechanisms of coupled folding and binding of intrinsically disordered proteins (IDPs), folding of monomeric globular proteins, folding of multimeric proteins, and ligand binding of globular proteins
The results revealed that many IDPs bind their partners by the induced-fit mechanism (Wright and Dyson 2009; Shammas et al 2016; Mollica et al 2016)
Summary
Elucidation of the mechanisms of protein folding and function remains an outstanding challenge in biophysics. The hydrophobic collapse model corresponds to an induced-fit mechanism, as compaction by binding of intramolecular segments precedes secondary and tertiary structure formation (Fig. 1b).
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