![]() ![]() In addition, most protein-protein interactions involve considerable buried surface area the peptides can only span a portion of this surface and hence generally have diminished binding affinity compared to the original binding partner. The requirement for a co-crystal structure with a binding partner limits the application of these methods because for many target proteins no such structure is available. Most current peptide binder design methods take advantage of one or more co-crystal structures of the target protein with a protein binding partner, and generate binders by stabilizing or scaffolding the interacting structural elements 20– 24, or mimicking 25 or enhancing the binding interface by amino acid substitions 26. Structure-based design of cyclic peptide binders has been more challenging. Due to limitations in synthesis, however, sampling the entirety of the chemical space is rarely possible and these libraries are limited to a subset of amino acids, often guided by the biochemical properties of the protein surface of interest. Library-based peptide discovery methods have been used to obtain molecules that bind to protein interfaces with high affinity 4, 10, 11, with considerable progress in terms of library size (currently up to 10 14), and ability to incorporate a variety of different amino acids 12– 16 and cyclization chemistries 17– 19. Cyclic peptides have been of particular interest due to their tunable rigidity, stability, and pharmacokinetics properties 4, 9. Peptides are emerging as a promising class of therapeutics with the potential to bind protein surfaces that are difficult to target using small molecules 1– 8. Additionally, the code used for design and instructions on how to run can be found in Peptide_HDACBinders folder in our github repository ( ). Instructions and inputs for running these applications, and all other data and coding necessary to support the results and conclusion are provided in extended data files 1. The Rosetta software suite is available free of charge to academic users and can be downloaded from. Source data are provided with this paper.Ĭonformational sampling was done with the Rosetta simple_cycpep_predict application and peptide design was carried out with the rosetta_scripts application, both of which are included in the Rosetta software suite. All relevant data are available from the authors upon request. 2– 5 and Supplementary Table 2) are available as a supplementary data file. The raw data for HDAC inhibition assays (presented in Figs. GUID: AAD8DCD8-972F-494C-AED2-DAE5649BB45B Data Availability StatementĪll the structures presented here are deposited in PDB with accession codes 6WHN, 6WHO, 6WHQ, 6WHZ, 6WI3, 6JSW. ![]()
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