{"doi":"10.1073/pnas.0707977104","title":"High-resolution design of a protein loop","abstract":"\n Despite having irregular structure, protein loops often adopt specific conformations that are critical to protein function. Most studies in\n de novo\n protein design have focused on creating proteins with regular elements of secondary structure connected by very short loops or turns. To design longer protein loops that adopt specific conformations, we have developed a protocol within the Rosetta molecular modeling program that iterates between optimizing the sequence and conformation of a loop in search of low-energy sequence–structure pairs. We have tested the procedure by designing 10-residue loops for the connection between the second and third strand in the β-sandwich protein tenascin. Three low-energy designs from 7,200 flexible backbone trajectories were selected for experimental characterization. All three designs, called LoopA, LoopB, and LoopC, adopt stable folded structures. High-resolution crystal structures of LoopA and LoopB have been solved. LoopB adopts a structure very similar to the design model (0.46 Å rmsd), and all but one of the side chains are modeled in the correct rotamers. LoopA crystallized at low pH in a structure that differs dramatically from our design model. It forms a strand-swapped dimer mediated by hydrogen bonds to protonated glutamic acids. Gel filtration indicates that the protein is not a dimer at neutral pH. These results suggest that the high-resolution design of protein loops is possible; however, they also highlight how small changes in protein energetics can dramatically perturb the low free energy structure of a protein.\n ","journal":"Proceedings of the National Academy of 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Kuhlman","orcid":"0000-0003-4907-9699","position":3,"is_corresponding":false},{"id":117212,"name":"Xiaozhen Hu","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.8283137373023015,"endowment":4.8283137373023015,"datacite_reuse_total":4,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"17971437","pmcid":"PMC2077077","openalex_id":"https://openalex.org/W2067576503","authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"GM073960","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM073960","title":null}],"total_grants":2,"fwci":4.1004,"citation_percentile":0.95142449,"influential_citations":4,"citation_trend":[{"year":2012,"count":7},{"year":2013,"count":9},{"year":2014,"count":6},{"year":2015,"count":9},{"year":2016,"count":7},{"year":2017,"count":7},{"year":2018,"count":5},{"year":2019,"count":5},{"year":2020,"count":15},{"year":2021,"count":4},{"year":2022,"count":5},{"year":2023,"count":4},{"year":2024,"count":3},{"year":2025,"count":4}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2077077","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc2077077?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2077077","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.0707977104","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.0707977104","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/17971437","host_type":"repository"}],"fields_of_study":["Enzyme Structure and Function","Protein Structure and Dynamics","RNA and protein synthesis mechanisms","Chemistry","Medicine","Biology","Amino Acid Sequence","Crystallography, X-Ray","Drug Design","Fibronectins","Models, Molecular","Peptide Fragments","Protein Conformation","Protein Denaturation","Proteins","Sensitivity and Specificity","Tenascin","Thermodynamics"],"mesh_terms":["Amino Acid Sequence","Fibronectins","Models, Molecular","Peptide Fragments","Protein Conformation","Protein Denaturation","Proteins","Sensitivity and Specificity","Thermodynamics","Drug Design","Crystallography, X-Ray","Tenascin"],"keywords":["Loop modeling","Protein design","Protein structure","Conformational isomerism","Crystallography","Dimer","Chemistry","Loop (graph theory)","Protein structure prediction","Hydrogen bond","Protein Data Bank (RCSB PDB)","Protein secondary structure","Protein folding","Protein crystallization","Stereochemistry","Molecule","Biochemistry","Mathematics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Affordable and clean energy"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.13487342.v1","title":"Additional file 1 of Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13487342","title":"Additional file 1 of Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13487348.v1","title":"Additional file 3 of Potentially adaptive SARS-CoV-2 mutations discovered with novel spatiotemporal and explainable AI models","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.13487348","title":"Additional file 3 of Potentially adaptive SARS-CoV-2 mutations discovered with 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