{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T05:02:16Z","timestamp":1785301336827,"version":"3.55.0"},"reference-count":270,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Aqueous two-phase systems (ATPSs) provide a versatile, fully aqueous platform for probing solute\u2013water interactions and protein structure. This review first surveys the diversity and phase behavior of biphasic aqueous systems formed by polymers and salts. We describe how phase diagrams characterize ATPS formation and composition and how both polymer chemistry and salt identity, rather than molecular size alone, govern phase separation by modulating the solvent properties of water. Building on a modified binodal model, we show that phase separation and solute partitioning can be understood in terms of changes in aqueous solvent dipolarity\/polarizability, hydrogen-bond donor\/acceptor properties, hydrophobicity, and electrostatics, quantified via solvatochromic probes and homologous solute series. These measurements underpin solvent interaction analysis (SIA), in which the partition coefficients of small molecules and proteins across panels of ATPSs are used to generate \u201cstructural signatures\u201d that sensitively report on amino acid substitutions, conformational changes, aggregation, ligand binding, osmolyte effects, and post-translational modifications, independent of protein size. We discuss how SIA can be implemented in vial-, plate-, and microfluidic formats and combined with diverse analytical readouts (HPLC, MS, colorimetric assays, and immunoassays), and we contrast this structure-focused approach with conventional concentration-only proteomic and biomarker strategies. Particular emphasis is placed on structure-based biomarker discovery, where disease-relevant shifts in proteoform distributions\u2014especially glycosylation changes\u2014are often more informative than bulk protein levels and where SIA can complement or simplify complex glycomics and top-down proteomics workflows. As a case study, we describe the recently FDA-approved IsoPSA assay, which applies SIA principles to prostate-specific antigen by measuring cancer-associated structural alterations in circulating PSA via its partition behavior in a proprietary ATPS. IsoPSA generates a single index that discriminates between high-grade prostate cancer and benign and low-grade conditions. Prospective, longitudinal, and MRI-integrated clinical studies demonstrate that IsoPSA improves pre-biopsy risk stratification, reduces unnecessary biopsies, and provides robust negative and positive predictive values within the PSA \u201cgray zone.\u201d Collectively, the data support aqueous solvent interaction analysis as a broadly applicable, mechanistically grounded technology for protein characterization, drug\u2013protein interaction studies, and structure-centric biomarker development, exemplified by the clinical translation of IsoPSA.<\/jats:p>","DOI":"10.3390\/ijms27156645","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Solvent Interaction Analysis: A New Lens for Protein Structure and Diagnostics"],"prefix":"10.3390","volume":"27","author":[{"given":"Boris Y.","family":"Zaslavsky","sequence":"first","affiliation":[{"name":"Cleveland Diagnostics, 3615 Superior Ave., Cleveland, OH 44114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Stovsky","sequence":"additional","affiliation":[{"name":"Cleveland Diagnostics, 3615 Superior Ave., Cleveland, OH 44114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4037-5857","authenticated-orcid":false,"given":"Vladimir N.","family":"Uversky","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Byrd Alzheimer\u2019s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","unstructured":"Albertsson, P.A. (1986). Partition of Cell Particles and Macromolecules, Wiley. [3rd ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9094","DOI":"10.1021\/ja303183z","article-title":"Aqueous multiphase systems of polymers and surfactants provide self-assembling step-gradients in density","volume":"134","author":"Mace","year":"2012","journal-title":"J. Am. Chem. 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