{"doi":"10.1021/jacs.3c09198","title":"The Energetic Origins of Pi–Pi Contacts in Proteins","abstract":"Accurate potential energy models of proteins must describe the many different types of noncovalent interactions that contribute to a protein's stability and structure. Pi-pi contacts are ubiquitous structural motifs in all proteins, occurring between aromatic and nonaromatic residues and play a nontrivial role in protein folding and in the formation of biomolecular condensates. Guided by a geometric criterion for isolating pi-pi contacts from classical molecular dynamics simulations of proteins, we use quantum mechanical energy decomposition analysis to determine the molecular interactions that stabilize different pi-pi contact motifs. We find that neutral pi-pi interactions in proteins are dominated by Pauli repulsion and London dispersion rather than repulsive quadrupole electrostatics, which is central to the textbook Hunter-Sanders model. This results in a notable lack of variability in the interaction profiles of neutral pi-pi contacts even with extreme changes in the dielectric medium, explaining the prevalence of pi-stacked arrangements in and between proteins. We also find interactions involving pi-containing anions and cations to be extremely malleable, interacting like neutral pi-pi contacts in polar media and like typical ion-pi interactions in nonpolar environments. Like-charged pairs such as arginine-arginine contacts are particularly sensitive to the polarity of their immediate surroundings and exhibit canonical pi-pi stacking behavior only if the interaction is mediated by environmental effects, such as aqueous solvation.","journal":"Journal of the American Chemical Society","year":2023,"id":319976,"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":52,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"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":728737,"name":"Meili Liu","orcid":"0009-0009-5324-2779","position":1,"is_corresponding":false},{"id":1029838,"name":"Leila Pujal","orcid":"0000-0002-1865-3478","position":2,"is_corresponding":false},{"id":270875,"name":"Matthias Loipersberger","orcid":"0000-0002-3648-0101","position":3,"is_corresponding":false},{"id":1029839,"name":"Maria Tsanai","orcid":"0000-0001-5137-4174","position":4,"is_corresponding":false},{"id":728740,"name":"Robert M. Vernon","orcid":"0000-0001-6479-2738","position":5,"is_corresponding":false},{"id":257869,"name":"Julie D. Forman‐Kay","orcid":"0000-0001-8265-972X","position":6,"is_corresponding":false},{"id":31711,"name":"Martin Head‐Gordon","orcid":"0000-0002-4309-6669","position":7,"is_corresponding":false},{"id":271509,"name":"Farnaz Heidar‐Zadeh","orcid":"0000-0002-2069-050X","position":8,"is_corresponding":false},{"id":257872,"name":"Teresa Head‐Gordon","orcid":"0000-0003-0025-8987","position":9,"is_corresponding":false},{"id":614484,"name":"Kevin Carter-Fenk","orcid":"0000-0001-8302-4750","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T01:07:17.361058Z","pmid":"37917924","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":[]}