{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T09:02:23Z","timestamp":1779958943999,"version":"3.53.1"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"China Ministry of Science and Technology","doi-asserted-by":"publisher","award":["2022YFC2105400"],"award-info":[{"award-number":["2022YFC2105400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Daptomycin, a lipopeptide antibiotic with critical clinical applications, presents a formidable crystallization challenge due to its high conformational flexibility and complex ionization equilibrium. Current literature lacks reports on single crystals or highly crystalline powders of this molecule. This study aims to elucidate the thermodynamic and kinetic mechanisms governing daptomycin solubility and crystallization to establish a rational screening pathway. Methods: In this study, the solubility of daptomycin was systematically measured across eight pure solvents using a static gravimetric method. Molecular-level insights were obtained by integrating experimental data with the Conductor-like Screening Model for Real Solvents (COSMO-RS) and molecular dynamics (MD) simulations. Results: Solubility trends correlated strongly with solvent electrostatic and hydrogen-bonding capabilities. MD simulations revealed that the solvent\u2019s ability to modulate conformational diversity\u2014quantified by the number of dominant conformational clusters\u2014is the decisive factor governing crystallization. For instance, aqueous systems exhibited strong Coulombic stabilization (\u22121126.61 kJ\/mol). Crucially, solvents like acetone restricted daptomycin to a limited number of conformers (12 clusters), significantly lowering the nucleation barrier and yielding crystalline powders with distinct PXRD peaks. Conversely, solvents like methanol induced high conformational diversity (53 clusters), resulting exclusively in amorphous precipitates. Conclusions: The \u201cnumber of conformational clusters\u201d serves as a robust descriptor for rapidly screening crystallization solvents, effectively bridging thermodynamics and kinetics. This strategy provides a rational, reduced-trial-and-error framework for crystallizing complex, flexible macromolecules with multiple dissociation sites, moving beyond traditional trial-and-error approaches.<\/jats:p>","DOI":"10.3390\/pharmaceutics18060657","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T08:00:36Z","timestamp":1779955236000},"page":"657","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformational Diversity-Driven Crystallization of Daptomycin: A Multi-Scale Approach with Experimental Validation"],"prefix":"10.3390","volume":"18","author":[{"given":"Qingshi","family":"Wen","sequence":"first","affiliation":[{"name":"College of Biotechnology and Pharmaceutical Engineering, National Engineering Technique Research Center for Biotechnology, Nanjing Tech University, No. 30, Puzhu South Road, Nanjing 211816, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Pharmaceutical Engineering, National Engineering Technique Research Center for Biotechnology, Nanjing Tech University, No. 30, Puzhu South Road, Nanjing 211816, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Pharmaceutical Engineering, National Engineering Technique Research Center for Biotechnology, Nanjing Tech University, No. 30, Puzhu South Road, Nanjing 211816, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyang","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Pharmaceutical Engineering, National Engineering Technique Research Center for Biotechnology, Nanjing Tech University, No. 30, Puzhu South Road, Nanjing 211816, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanjie","family":"Ying","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Pharmaceutical Engineering, National Engineering Technique Research Center for Biotechnology, Nanjing Tech University, No. 30, Puzhu South Road, Nanjing 211816, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengpeng","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Biotechnology and Pharmaceutical Engineering, National Engineering Technique Research Center for Biotechnology, Nanjing Tech University, No. 30, Puzhu South Road, Nanjing 211816, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.jsb.2006.09.006","article-title":"Searching for silver bullets: An alternative strategy for crystallizing macromolecules","volume":"156","author":"Mcpherson","year":"2006","journal-title":"J. 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