In new work published in Journal of Chemical Information and Modeling, Ge et al. use molecular simulation study the binding mechanism of four designed cyclic β-hairpin ligands of the MDM2 receptor. These peptides, first characterized by the Mate Erdelyi group at the University of Uppsala, show different amounts of conformational flexibility in solution, and a range of binding affinities. By constructing Markov State Models (MSMs) of these peptides in solution, and binding to MDM2, we strikingly find that the difference in binding affinity can be entirely explained by the extent of preorganization (i.e. folding propensity) of these peptides in solution. This work has big implications for the possibility of designing solution-state folding properties to enhance the binding affinity of peptidomimetics.
We also show improved estimates of slow dissociation rates by using biased simulations (umbrella sampling) along with Multi-ensemble Markov models (MEMMs).
Read more in our paper “Solution-State Preorganization of Cyclic β-Hairpin Ligands Determines Binding Mechanism and Affinities for MDM2″ here: https://pubs.acs.org/doi/10.1021/acs.jcim.1c00029