{"doi":"10.1101/2023.03.15.532709","title":"What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks","abstract":"Abstract Identifying critical residues in protein-protein binding and efficiently designing stable and specific protein binders is challenging. In addition to direct contacts in a protein-protein binding interface, our study employs computation modeling to reveal the essential network of residue interaction and dihedral angle correlation critical in protein-protein recognition. We propose that mutating residues regions exhibited highly correlated motions within the interaction network can efficiently optimize protein-protein interactions to create tight and selective protein binders. We validated our strategy using ubiquitin (Ub) and MERS coronaviral papain-like protease (PLpro) complexes, where Ub is one central player in many cellular functions and PLpro is an antiviral drug target. Our designed UbV with 3 mutated residues resulted in a ∼3,500-fold increase in functional inhibition, compared with the wild-type Ub. Further optimization by incorporating 2 more residues within the network, the 5-point mutant achieved a K D of 1.5 nM and IC 50 of 9.7 nM. The modification led to a 27,500-fold and 5,500-fold enhancements in affinity and potency, respectively, as well as improved selectivity, without destabilizing the UbV structure. Our study highlights residue correlation and interaction networks in protein-protein interaction, introduces an effective approach to design high affinity protein binders for cell biology and future therapeutics solutions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":394305,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1096967,"name":"Yun-Jung Hsieh","orcid":"0009-0005-1687-3273","position":1,"is_corresponding":false},{"id":1097445,"name":"Wei-Lin Lu","orcid":null,"position":2,"is_corresponding":false},{"id":327108,"name":"Kuen‐Phon Wu","orcid":"0000-0002-1525-6004","position":3,"is_corresponding":false},{"id":327109,"name":"Chia‐en A. Chang","orcid":"0000-0002-6504-8529","position":4,"is_corresponding":false},{"id":1096966,"name":"Ta I Hung","orcid":"0009-0008-9702-3829","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T01:19:10.334330Z","pmid":"36993448","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}