A computational protein design protocol for optimization of the SARS-CoV-2 receptor-binding-motif affinity for human ACE2

The present protocol describes the computational design of the SARS-CoV-2 receptor binding motif (RBD) to identify mutations that can potentially improve binding affinity for the human ACE2 (hACE2) receptor. We focus on four positions located at the interface with the hACE2 receptor in the RBD:hACE2 complex. We conduct the design with a high-throughput computational protein design (CPD) program, Proteus, incorporating an adaptive Monte Carlo (MC) protocol that promotes the selection of sequences with good binding affinities. For complete details on the use and execution of this protocol, please refer to Polydorides and Archontis (2021).