In the following, we report the simulation results together with experimental results. We assess the absolute residence time predictions with RMSE and the relative residence times with R 2 and Spearman ρ. All metrics are calculated using the log 10 of the simulated and experimental times. An important measure of iMetaD reliability is the percentage of simulations that successfully unbind. A simulation is deemed unsuccessful when the residence time value from a single iMetaD simulation calculated using Eq. 6 reaches 10 10 s. In this case, the simulation is automatically terminated to spare computational resources. This may occasionally happen because an orthogonal degree of freedom would emerge and prevent an unbinding event from occurring. Hence this number is a useful proxy of the system being within the domain of applicability of the method. We also report the P-value of the Kolmogorov-Smirnoff test. This value represents how much the cumulative distribution resembles a first-order transition. It is widely known that protein unbinding is a multistep process so we use this value as a descriptor of the process, hence we mostly expect values <0.05. It is interesting to observe that for some systems (vide infra) we occasionally measure larger values typical of an effective-first order process in the space of path CVs.