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

preprint
revised on 19.04.2021, 14:53 and posted on 20.04.2021, 06:01 by Yunhui Ge, Si Zhang, Mate Erdelyi, Vincent Voelz

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 timescales. Consideration of 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 disrupt the MDM2-p53 interaction. MSM analysis of over 3 ms of aggregate trajectory data enabled us to build a detailed mechanistic model of coupled folding and binding of four cyclic peptides which we compare to experimental binding affinities and rates. The results show a striking relationship between the relative preorganization of each ligand in solution and its affinity for MDM2. Specifically, changes in peptide conformational populations predicted by the MSMs suggest that entropy loss upon binding is the main factor influencing affinity. The MSMs also enable detailed examination of non-native interactions which lead to misfolded states, and comparison of structural ensembles with experimental NMR measurements. In contrast to an MSM study of p53 TAD binding to MDM2, MSMs of cyclic β-hairpin binding show a conformational selection mechanism. Finally, we make progress towards predicting accurate off-rates of cyclic peptides using multiensemble Markov models (MEMMs) constructed from unbiased and biased simulated trajectories.

Funding

1S10OD020095-01

1R01GM123296-01

W911NF-16-2-0189

History

Email Address of Submitting Author

yunhui.ge@gmail.com

Institution

University of California, Irvine

Country

United States

ORCID For Submitting Author

0000-0002-3946-1440

Declaration of Conflict of Interest

N/A

Version Notes

version 3 (final version)

Exports