The p53 pathway is involved in cell death, and its malfunctioning is related to tumor growth. MDM2 and its analogue MDMX bind with an intrinsically disordered domain of p53 and are overexpressed in cancerous cells. Understanding the binding mechanism: conformational selection, induced fit or a mixture of the two, can help design potential drugs.<br/><br/>The crystallographic p53-bound structure to MDM2/X exhibits a helical conformation. Using MELD, a Bayesian inferences accelerated Molecular Dynamics modelling, we simulated the binding between MDM2 and 5 peptides individually. Among the native p53 peptide, an experimentally selected good binder PDIQ, a stapled helical peptide ATSP, and two alanine- based peptides as a baseline to the study, those peptides with high population of helical conformation (bound structure) result in significant binding, indicating that conformation of the peptide plays an important role in binding.<br/><br/>We are also building a Markov state model to show the binding pathway of the native p53 peptide and MDM2. Using the rates generated by MSM, we want to construct a kinetic model of how the peptide diffuses near the binding site, weakly associating with it and eventually binding strongly to MDM2. From our studies about pathways and binding mechanisms of the peptides we aim to identify characteristics that might lead to more effective inhibitors

Mechanistic insights: Lessons for drug design from simulations of peptide binding

ACS Spring Meeting 2021

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