Effect of introducing aib in a designed helical inhibitor of hdm2-p53 interaction: A molecular dynamics study

Abstract

Although p53 is an intrinsically disordered protein, upon binding to Hdm2, a short stretch (residues 19-25) comprising the binding epitope assumes a helical backbone. Because the allowed conformational space of α-aminoisobutyric acid (Aib) is restricted to only the helical basin, Aib-containing helical mimics of p53 (binding epitope) are expected to inhibit interaction between p53 and Hdm2 with a much stronger affinity than the wild type p53 peptide (binding epitope), due to the entropic advantage associated with Aib. However, the IC50 values for the disruption of p53-Hdm2 interaction by Aib-p53 peptides and wild type p53 peptide were found to be comparable (J. Peptide Res. 2002, 60:88-94). To understand why incorporation of Aib didn't substantially increase Hdm2 affinity of Aib-p53 peptides, a series of molecular dynamics simulations were performed. It was found that despite stabilizing a helical backbone in the unbound state, the Aib residues in Aib-p53 peptide arrested two functionally important side-chains (F19 and W23) in non-productive conformations, resulting in relative side-chain orientations of the binding triad F19-W23-L26 incompatible with the bound conformation. Therefore, although a Aib-induced pre-formed helical peptide backbone in the unbound state is expected to favor binding, the locked side-chain orientations of the binding triad in non-productive modes would disfavor binding. This study shows that when using Aib to design functionally important helical peptides, care must be taken to consider potential interactions between side-chains of neighboring residues and Aib in the unbound state.