Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites.

Despite recent success in computational design of structured cyclic peptides, de novo design of cyclic peptides that bind to any protein functional site remains difficult. To address this challenge, we develop a computational "anchor extension" methodology for targeting protein interfaces by extending a peptide chain around a non-canonical amino acid residue anchor. To test our approach using a well characterized model system, we design cyclic peptides that inhibit histone deacetylases 2 and 6 (HDAC2 and HDAC6) with enhanced potency compared to the original anchor (IC values of 9.

Macromolecular modeling and design in Rosetta: recent methods and frameworks.

The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities.

Integration of the Rosetta suite with the python software stack via reproducible packaging and core programming interfaces for distributed simulation.

The Rosetta software suite for macromolecular modeling is a powerful computational toolbox for protein design, structure prediction, and protein structure analysis. The development of novel Rosetta-based scientific tools requires two orthogonal skill sets: deep domain-specific expertise in protein biochemistry and technical expertise in development, deployment, and analysis of molecular simulations. Furthermore, the computational demands of molecular simulation necessitate large scale cluster-based or distributed solutions for nearly all scientifically relevant tasks.