Abstract
The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the past decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development of adaptive (smart) therapeutics. Here, a computational strategy is developed to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), the templates are gradually modified by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide libraries of optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale.