Solution-State Preorganization of Cyclic β-Hairpin Ligands Determines Binding Mechanism and Affinities for MDM2.

ABSTRACT: Understanding mechanisms of protein folding and binding is crucial to designing their molecular function. Molecular dynamics (MD) simulations and Markov state model (MSM) approaches provide a powerful way to understand complex conformational change that occurs over long time scales. Such dynamics are important for the design of therapeutic peptidomimetic ligands, whose affinity and binding mechanism are dictated by a combination of folding and binding. To examine the role of preorganization in peptide binding to protein targets, we performed massively parallel explicit-solvent MD simulations of cyclic β-hairpin ligands designed to mimic the p53 transactivation domain and competitively bind mouse double minute 2 homologue (MDM2). Disrupting the MDM2-p53 interaction is a therapeutic strategy

SUBMITTER: Ge Y 

PROVIDER: S-EPMC9960209 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature