Fig. 1. Outline of our algorithm for designing sequences of IDPs with targeted conformational properties.

As the starting point, we here use naturally occurring IDP sequences, although this is not a requirement of the approach. We use MD simulations with the coarse-grained CALVADOS force field to describe the IDPs and to generate a conformational ensemble. New sequences are proposed through an MCMC scheme. We evolve the sequences by consecutive swaps in positions between two randomly selected residues and evaluate if the sequences get closer or further away from the design target—here chain compaction. During sequence optimization, we calculate the conformational properties for a given sequence by either direct simulations or alchemical calculations that rely on conformational ensembles of previously sampled sequences. The conformations shown have the same radius of gyration as the average of the conformational ensemble.