Fig. 7: Thermodynamic and kinetic analysis of ternary complex simulations.

a Conformational free energy landscapes of the iso2-SMARCA2^BD:PROTAC 1:VHL, iso2-SMARCA2^BD:PROTAC 2:VHL, and iso2-SMARCA2^BD:ACBI1:VHL systems in the PCA space defined by our analysis of HREMD simulations. The crystal structure of each system is shown as a dark blue X, while the center of the largest k-means cluster is shown as a green point. Energy scale bar shown in panel b. b Conformational free energy landscape as a function of the first two tICA features of iso2-SMARCA2^BD:PROTAC 2:VHL ternary complex inferred from a Markov state model (MSM) determined using long-timescale Folding@home simulations. The ensemble of bound states from WE-HDX simulations is shown as blue points; the crystal structure (PDB ID: 6HAX) is shown as a red X. In this projection, states II and V are not indicated but are close to state I. c Network diagram of the coarse-grained MSM calculated using a lag time of 50 ns, with the stationary probabilities associated with each state indicated. d Mean first-passage times (MFPTs) to transition between MSM states. Numbers indicate predicted MFPTs in μs. e Comparison of the crystal structure (salmon) with the lowest free energy state (blue) and a metastable state (red) predicted by the MSM. Arrows indicate the change of orientation by 90°.