Abstract
The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the ‘conformational selection’ paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by ‘binding induced folding’. This hypothesis is further supported by pulling simulations that pull the peptides away from their bound states with MDM2. This data extends the earlier mechanisms proposed to rationalize the entropically driven binding of the p53 set and the enthalpically driven binding of the 12/1 set. Using our hypothesis, we suggest mutations to the 12/1 peptide that increase its helicity in simulations and may, in turn, shift the binding towards conformational selection. In summary, understanding the conformational landscapes of the MDM2-binding peptides may suggest new peptide designs with bespoke binding mechanisms.
Highlights
P53 is a transcription factor that plays a central role in cell cycle regulation
All small molecule and peptidic inhibitors to date have been found to mimic the interactions between these 3 N-terminal transactivation domain (NTD) residues and MDM2
The 12/1 set is more disordered in solution, incurs a large reorganizational penalty upon binding, and compensates by making more stabilizing interactions with MDM2
Summary
A particular state, where the Asp[21] to Leu[26] region is helical, is significantly populated in the p53-P27N simulations In this intermediate Phe[19], one of the key residues involved in binding with MDM2, is not in the helical form (Fig. 3c). Our study suggests that the 12/1 peptide has a rugged energy landscape and its sequence is not optimal to fold into an α-helix In the simulations, it populates different structures including β-sheets which are known for their aggregation propensities[39]. It is clear that this method will not exhaustively sample the different directions of approach/exit of the peptide to/ from the surface of MDM2 It can provide some insights into the conformations adopted by the peptides at increasing distances from the receptor (as has been shown in our laboratory earlier for the disordered C-terminus of p53 binding to multiple receptors24), which should approximate the behaviour of the peptides in solution. While this does not comment on the putative interactions between the lid and the peptides totally, especially at the C-terminus end of the peptides as they are located closer to the lid region and are known to have allosteric effects[1], it suggests that 1YCR lacking the lid, is a good model system for understanding the interactions between MDM2 and peptides
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