Funnel metadynamics simulations were explored as a means to improve sampling and reproducibility among replicates. A custom funnel design was implemented in OpenMM inspired by the approach followed by Hedges et al. (Figure ). Funnel metadynamics simulations of CC-Di, apCC-Di and CC-Tri were run for 1 µs with three independent replicates. A range of different funnel parameters were tested on each complex. Further details about the setup of funnel metadynamics simulations are provided in the SI (SI Section 4).