Abstract
Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape. We suggest that such ‘intrinsically disordered’ landscapes, with a number of very different competing low-energy structures, are likely to characterise IDPs, and provide a useful way to address their properties. In particular, IDPs are present in many cellular protein interaction networks, and several questions arise regarding how they bind to partners. Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? We focus on the p53 upregulated modulator of apoptosis (PUMA) protein, which adopts an -helical conformation when bound to its partner, and is involved in the activation of apoptosis. Recent experimental evidence shows that folding is not necessary for binding, and supports an induced-fit mechanism. Using a variety of computational approaches we deduce the molecular mechanism behind the instability of the PUMA peptide as a helix in isolation. We find significant barriers between partially folded states and the helix. Our results show that the favoured conformations are molten-globule like, stabilised by charged and hydrophobic contacts, with structures resembling the bound state relatively unpopulated in equilibrium.
Highlights
Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape
Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? We focus on the p53 upregulated modulator of apoptosis (PUMA) protein, which adopts an α-helical conformation when bound to its partner, and is involved in the activation of apoptosis
To obtain some initial insight into the 32-residue PUMA peptide when isolated, we performed 600 ns molecular dynamics simulations starting from the contiguous helical structure at 280 and 300 K in explicit solvent (Fig. 1)
Summary
Analysis of an intrinsically disordered protein (IDP) reveals an underlying multifunnel structure for the energy landscape. Are conformations resembling the bound structure selected for binding, or does further folding occur on binding the partner in a induced-fit fashion? From a structural point of view, disordered proteins are noteworthy in undergoing a disorder-to-order transition upon binding to a partner, referred to as the ‘coupled folding and binding mechanism’[13,14] This binding mechanism rules out a lock-and-key scenario, highlighting a key question: does binding occur through conformational selection or induced-fit? In the first case the binding partner selects a conformation closely related to the IDP-bound conformation, not necessarily most populated in the unbound ensemble In the latter case, the binding partner induces structure and folding of the disordered protein upon contact. The NCBD disordered protein binds two different partners, mainly through an induced-fit recognition mechanism, the authors do not exclude an alternative conformational selection pathway for binding[17]
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