{"doi":"10.1016/j.jbc.2021.100974","title":"Letting go: Deep computational modeling insights into pH-dependent calcium affinity","abstract":"Calcium and other cofactors can feature as key additions to a molecular interface, to the extent that the cofactor is completely buried in the bound state. How can such an interaction be regulated then? The answer: By facilitating a switch through an allosteric network. Although a number of unbinding mechanisms are being characterized, an extensive computational study by Joswig et al. reveals a detailed model for the pattern recognition receptor langerin. Calcium and other cofactors can feature as key additions to a molecular interface, to the extent that the cofactor is completely buried in the bound state. How can such an interaction be regulated then? The answer: By facilitating a switch through an allosteric network. Although a number of unbinding mechanisms are being characterized, an extensive computational study by Joswig et al. reveals a detailed model for the pattern recognition receptor langerin. “Sometimes it’s hard to let go”, is a life truth many people experience. It is also true at the molecular level when complexes between a protein and its ligand or between a protein and another protein or macromolecule need to dissociate as part of a functional cycle. The mechanisms which comprise unbinding processes have only just recently been studied in detail, in part due to the advent of advanced, if not extensive, molecular dynamics (MD) simulations (1Ribeiro J.M.L. Tsai S.T. Pramanik D. Wang Y. Tiwary P. Kinetics of ligand-protein dissociation from all-atom simulations: Are we there yet?.Biochemistry. 2019; 58: 156-165Crossref PubMed Scopus (23) Google Scholar, 2Zhang L. Borthakur S. Buck M. Dissociation of a dynamic protein complex studied by all-atom molecular simulations.Biophys. J. 2016; 110: 877-886Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar) and experimental techniques with high time/spatial resolution, such as NMR spectroscopy (3Rosenzweig R. Kay L.E. Solution NMR spectroscopy provides an avenue for the study of functionally dynamic molecular machines: The example of protein disaggregation.J. Am. Chem. Soc. 2016; 138: 1466-1477Crossref PubMed Scopus (22) Google Scholar). The general questions in this field include: Is the dissociation process multistep? What are the thermodynamic driving forces? What is the level of kinetic versus thermodynamic control? There are likely many unbinding processes, given the great diversity of protein and (macro-)molecular interfaces. Therefore, it is a good strategy to focus on interfaces which have features in common, such as divalent cations (particularly magnesium and calcium), which are cofactors for many proteins. Both of these ions play critical roles in a vast arena of protein functions which are increasingly well characterized at the molecular level. For example, serum calcium can be sensed to exquisite accuracy by the extracellular Ca2+-sensing receptor, which presents a connection between Ca2+ binding and allosteric modulators, agonists, and antagonists for this seven transmembrane G-protein coupled receptor protein. The list of receptors of which Ca2+ and Mg2+ play a role in regulation is growing, including ryanodine, adenosine, and opiod receptors representing other recently studied cases. However, mechanisms can become even more intriguing when another common cellular component is involved. Such is the case with a transmembrane potential in mammalian Ca2+ and voltage-activated K+ channels, or for the protein at the center of this JBC Editor’s pick, the C-type lectin receptor langerin, whose carbohydrate binding is sensitive to both Ca2+ concentration and pH. The C-type lectin receptor langerin is a key defense in mammals against invading pathogens. The trimeric langerin receptor on the host membrane binds to carbohydrates on the virus surface and then the langerin–virus complex is endocytosed and trafficked to an acidic endosome where it is released in a pH- and calcium-dependent manner and degraded. Despite the high level of interest in this sy","journal":"Journal of Biological Chemistry","year":2021,"id":225819,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":215982,"name":"Matthias Buck","orcid":"0000-0002-2958-0403","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-18T23:54:30.292454Z","pmid":"34280436","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":[]}