The initial simulation temperature, T 0 , starts at the same order of magnitude as the random structure energy distribution, to ensure high energy moves are accepted early on in the simulation. To ensure the annealing process spends sufficient time in both the exploratory and exhaustive regimes, we select an annealing rate, r a , to slowly transitions between the two regimes. The transitions vary from model to model and can give insight into the surface being sampled. We share and examine different transitions in Supporting Information sec-sampled at each T i and the number of annealing cycles, M , is chosen such that the final temperature, T M is 2-3 orders of magnitude below the initial energy of the foldamer. Figure shows an example of the trajectories of energy over the annealing process. At high temperatures, energies have large fluctuations as the foldamer model explores many configurations.