Computational Design of Structured and Functional Peptide Macrocycles

Structure-based computational design methods have been developed to create proteins in silico with diverse shapes and sizes that accurately fold in vitro, from 7-residue macrocycles to megadalton-scale self-assembling nanomaterials. Precise control over protein shape has further enabled design and optimization of functional therapeutic proteins, including agonists, antagonists, enzymes, and vaccines. Computational design of functional peptides of smaller size presents a persistent challenge, with few successful examples to date. Herein we describe validated general methods for computational design of peptides using the Rosetta molecular modeling suite and discuss outstanding challenges and future directions.