CORE SUMMARY This Core is designed to provide CHEETAH Center members with access to novel approaches for making, manipulating, and identifying new biomolecules relevant to studies of different HIV-host systems under investigation in our Center. Specifically, our Tools for Biopolymer Synthesis and Screening Core (Core 1) will develop new methodology and provide Center members with access to state-of-the-art instrumentation and expertise in Peptide Synthesis, Protein Design, and CRISPR Screening Methodology. Component 1 (Peptide Synthesis) will provide synthetic peptide and protein reagents that are not readily accessible using traditional recombinant expression systems. Since chemical synthesis provides complete atomic control over the composition of peptides/proteins, this method is ideal for producing custom reagents containing labels (fluorophores, isotopes), modifications (methylation, phosphorylation), and non-canonical components (mirror-image or other unusual amino acids, cyclic or crosslinked peptides/proteins). Additionally, this Core will continue to develop novel chemical peptide synthesis tools to expand the reach of chemical protein synthesis to larger and more challenging targets. Component 2 (Protein Design) will collaborate with CHEETAH Center laboratories to use and extend cutting-edge computational protein design methodologies to generate novel protein tools, reagents, and platforms in support of HIV-1 research. Specific advances will include incorporating deep learning methods into protein design pipelines and applying the enhanced design approaches to optimize target protein expression, stability, and homogeneity. Component 3 (CRISPR Screening Methodology) will perform CRISPR validation experiments and HIV-CRISPR screens with existing CRISPR libraries, and also develop novel libraries to identify candidate host genes implicated in phenotypes of interest to CHEETAH Center laboratories. The overall goals are to: 1) uncover and highlight functionally relevant host protein targets for further study, and 2) provide expertise for functional validation studies.