On-the-Fly Sequential Design of Simple Peptides

We introduce a simple and efficient computational methodology capable of designing peptides lacking higher order structures. The method is based on the sequential modification of residues in a simple peptide attached to a substrate of interest. The peptide design can start at an arbitrary point of the substrate and proceed into a direction chosen spontaneously or guided by an external potential. The decision about using a certain residue is based on its binding free energy to the substrate, as evaluated in molecular dynamics simulations. Here, this approach is tested on the design of peptides binding to spike proteins in SARS-CoV-2. The methodology can be easily modified according to actual needs and extended to other molecules.