{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T19:15:50Z","timestamp":1788290150657,"version":"build-2803163510"},"reference-count":22,"publisher":"American Chemical Society (ACS)","issue":"34","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000078","name":"Division of Materials Research","doi-asserted-by":"publisher","award":["DMR-XC-1757749"],"award-info":[{"award-number":["DMR-XC-1757749"]}],"id":[{"id":"10.13039\/100000078","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000078","name":"Division of Materials Research","doi-asserted-by":"publisher","award":["DMR-XC-2049793"],"award-info":[{"award-number":["DMR-XC-2049793"]}],"id":[{"id":"10.13039\/100000078","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000152","name":"Division of Molecular and Cellular Biosciences","doi-asserted-by":"publisher","award":["MCB-2221796"],"award-info":[{"award-number":["MCB-2221796"]}],"id":[{"id":"10.13039\/100000152","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Understanding how amino acid residues partition from water into lipid bilayers is fundamental to membrane protein folding, stability, and function. Existing hydrophobicity scales derive from isolated protein systems, organic solvent approximations, or computationally expensive free energy methods, each with significant limitations in capturing the full thermodynamic and topographic complexity of membrane protein environments. Here we present a lipid-shell modification to the protocol for assigning a residue\u2019s character on a hydropathy (PARCH) scale, in which the protein\u2019s first hydration shell is enclosed by a lipid boundary layer during thermal annealing. This modification preserves the core PARCH methodology\u2500evaluating water retention around residues as a function of temperature\u2500while imposing the chemical potential boundary condition appropriate for membrane-embedded proteins. Using the OmpLA host\u2013guest system, we compute PARCH values (PVs) that align with the experimental water-to-bilayer transfer free energy scale of Moon and Fleming (PNAS, 108, 10174\u201310177, 2011) without calibration to that data. We further demonstrate that depth-dependent PV profiles for arginine and leucine mirror experimentally measured partition energies across six membrane positions. Finally, PVs for a tandem arginine double mutant reveal a per-residue cooperative hydration redistribution that provides microscopic insight into thermodynamic cooperativity previously measured experimentally. Together, these results establish the lipid-shell PARCH modification as a computationally affordable and physically meaningful approach to quantifying membrane hydropathy that is sensitive to residue identity, membrane depth, and cooperative hydration among tandem charged residues.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c03679","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T14:02:46Z","timestamp":1786629766000},"page":"8616-8623","source":"Crossref","is-referenced-by-count":0,"title":["Lipid-Shell PARCH:\nA Physically Motivated Scale for\nTransmembrane Residue Hydropathy"],"prefix":"10.1021","volume":"130","author":[{"given":"Ratnakshi","family":"Mandal","sequence":"first","affiliation":[{"name":"Syracuse University , , , ,","place":["Syracuse, New York, United States, 13244"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1170-8461","authenticated-orcid":true,"given":"Shikha","family":"Nangia","sequence":"additional","affiliation":[{"name":"Syracuse University , , , ,","place":["Syracuse, New York, United States, 13244"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"4","key":"2026090114353077800_cit1","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1002\/pro.5560070420","article-title":"Genome-wide analysis of integral membrane proteins\nfrom eubacterial, archaean, and eukaryotic organisms","volume":"7","author":"Wallin","year":"1998","journal-title":"Protein Sci."},{"issue":"6","key":"2026090114353077800_cit2","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1002\/pmic.200900258","article-title":"Prediction of the human membrane proteome","volume":"10","author":"Fagerberg","year":"2010","journal-title":"Proteomics"},{"issue":"2","key":"2026090114353077800_cit3","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/s41580-021-00413-2","article-title":"The mechanisms of integral membrane protein biogenesis","volume":"23","author":"Hegde","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"1","key":"2026090114353077800_cit4","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1146\/annurev-biophys-070524-100658","article-title":"Emerging\nPatterns in Membrane Protein Folding Pathways","volume":"54","author":"Kim","year":"2025","journal-title":"Annu. Rev. Biophys."},{"issue":"3","key":"2026090114353077800_cit5","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202153025","article-title":"How physical forces\ndrive the process of helical membrane\nprotein folding","volume":"23","author":"Corin","year":"2022","journal-title":"EMBO Rep."},{"key":"2026090114353077800_cit6","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.sbi.2021.03.006","article-title":"Membrane proteins enter the fold","volume":"69","author":"Marx","year":"2021","journal-title":"Curr. Opin. Struct. Biol."},{"issue":"2","key":"2026090114353077800_cit7","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1021\/jacs.0c09412","article-title":"Local Bilayer Hydrophobicity Modulates\nMembrane Protein\nStability","volume":"143","author":"Marx","year":"2021","journal-title":"J. Am. Chem. Soc."},{"issue":"2","key":"2026090114353077800_cit8","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.bbamem.2011.07.016","article-title":"Outer membrane\nphospholipase A in phospholipid bilayers: A model system for concerted\ncomputational and experimental investigations of amino acid side chain\npartitioning into lipid bilayers","volume":"1818","author":"Fleming","year":"2012","journal-title":"Biochim. Biophys.\nActa Biomembr."},{"issue":"2","key":"2026090114353077800_cit9","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.jmb.2011.08.041","article-title":"Overcoming hysteresis\nto attain reversible\nequilibrium folding for outer membrane phospholipase A in phospholipid\nbilayers","volume":"413","author":"Moon","year":"2011","journal-title":"J. Mol. Biol."},{"issue":"1","key":"2026090114353077800_cit10","doi-asserted-by":"publisher","first-page":"4863","DOI":"10.1038\/ncomms5863","article-title":"Spontaneous transmembrane helix insertion thermodynamically\nmimics translocon-guided insertion","volume":"5","author":"Ulmschneider","year":"2014","journal-title":"Nat. Commun."},{"issue":"6","key":"2026090114353077800_cit11","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.neuron.2010.08.021","article-title":"Ion Channel\nVoltage Sensors: Structure, Function, and Pathophysiology","volume":"67","author":"Catterall","year":"2010","journal-title":"Neuron"},{"issue":"4","key":"2026090114353077800_cit12","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/nrm2376","article-title":"How membrane\nproteins sense voltage","volume":"9","author":"Bezanilla","year":"2008","journal-title":"Nat. Rev. Mol. Cell\nBiol."},{"issue":"3","key":"2026090114353077800_cit13","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/j.neuron.2004.12.047","article-title":"Voltage-Sensing\nArginines in a Potassium\nChannel Permeate and Occlude Cation-Selective Pores","volume":"45","author":"Tombola","year":"2005","journal-title":"Neuron"},{"issue":"8","key":"2026090114353077800_cit14","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.3390\/toxins5081362","article-title":"pH-Triggered\nConformational Switching along the Membrane Insertion Pathway of the\nDiphtheria Toxin T-Domain","volume":"5","author":"Ladokhin","year":"2013","journal-title":"Toxins"},{"issue":"1","key":"2026090114353077800_cit15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev.cellbio.19.111301.140655","article-title":"Anthrax Toxin","volume":"19","author":"Collier","year":"2003","journal-title":"Annu. Rev. Cell\nDev. Biol."},{"issue":"25","key":"2026090114353077800_cit16","doi-asserted-by":"publisher","first-page":"10174","DOI":"10.1073\/pnas.1103979108","article-title":"Side-chain hydrophobicity\nscale derived from transmembrane\nprotein folding into lipid bilayers","volume":"108","author":"Moon","year":"2011","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"4","key":"2026090114353077800_cit17","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1021\/acs.jctc.3c00106","article-title":"An Affordable Topography-Based\nProtocol for Assigning a Residue\u2019s Character on a Hydropathy\n(PARCH) Scale","volume":"20","author":"Ji","year":"2024","journal-title":"J. Chem. Theory Comput."},{"issue":"42","key":"2026090114353077800_cit18","doi-asserted-by":"publisher","first-page":"22049","DOI":"10.1021\/acs.langmuir.4c02142","article-title":"Nanoscale Topography Dictates Residue\nHydropathy in Proteins","volume":"40","author":"Ji","year":"2024","journal-title":"Langmuir"},{"issue":"26","key":"2026090114353077800_cit19","doi-asserted-by":"publisher","first-page":"16874","DOI":"10.1021\/acs.langmuir.5c01051","article-title":"Introducing\nthe PARCH Scale for Quantifying the Hydropathy of Nucleic Acids and\nNucleic Acid\u2013Protein Complexes","volume":"41","author":"Mandal","year":"2025","journal-title":"Langmuir"},{"issue":"14","key":"2026090114353077800_cit20","doi-asserted-by":"publisher","first-page":"3844","DOI":"10.1021\/acs.jpcb.6c00520","article-title":"Hydropathy Landscapes\nof Histone\u2013DNA Interactions in Chromatin Building Blocks","volume":"130","author":"Mandal","year":"2026","journal-title":"J. Phys. Chem. B"},{"issue":"7","key":"2026090114353077800_cit21","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1021\/acs.jpcb.5c08630","article-title":"Decoding the Post-translational Modification Crosstalk:\nFunctional Implications of Phosphorylation, Acetylation, and Methylation","volume":"130","author":"Qin","year":"2026","journal-title":"J. Phys. Chem. B"},{"issue":"6","key":"2026090114353077800_cit22","doi-asserted-by":"publisher","first-page":"2999","DOI":"10.1021\/acs.jcim.4c02415","article-title":"Extending the PARCH\nScale: Assessing\nHydropathy of Proteins across Multiple Water Models","volume":"65","author":"Qin","year":"2025","journal-title":"J. Chem. Inf. Model."}],"container-title":["The Journal of Physical\nChemistry B"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jpcb.6c03679","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/34\/8616\/66527125\/acs.jpcb.6c03679.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article-pdf\/130\/34\/8616\/66527125\/acs.jpcb.6c03679.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:35:40Z","timestamp":1788287740000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jpcbfk\/article\/130\/34\/8616\/5254335\/Lipid-Shell-PARCH-A-Physically-Motivated-Scale-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":22,"journal-issue":{"issue":"34","published-online":{"date-parts":[[2026,8,13]]},"published-print":{"date-parts":[[2026,8,27]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jpcb.6c03679","relation":{},"ISSN":["1520-6106","1520-5207"],"issn-type":[{"value":"1520-6106","type":"print"},{"value":"1520-5207","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}