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Insights into Mcl-1 Conformational States and Allosteric Inhibition Mechanism from Molecular Dynamics Simulations, Enhanced Sampling, and Pocket Crosstalk Analysis

In this study, we explored the structural dynamics of Mcl-1: an anti-apoptotic protein. Based on structural ensembles, essential dynamics were extracted and showed two major axes of variability: a breathing motion at the binding interface and a correlated motion through the internal loops. A free-energy surface characterizing the breathing motion at the binding interface was generated and suggested an equilibrium between a closed and a "ready to bind" conformation as the predominant states of Mcl-1 in solution. Moreover, the analysis of the dynamics along the internal loops revealed a hidden communication network of transient and cryptic pockets controlling the allosteric inhibition of Mcl-1. A detailed model, joining the pockets crosstalk and salt bridge networks along the internal loops was proposed and allowed us to shed light on the key interactions governing Mcl-1's allosteric inhibition.