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Conformational Diversity-Driven Crystallization of Daptomycin: A Multi-Scale Approach with Experimental Validation
Qingshi Wen1, Ke Zhang1, Li Huang1
1College of Biotechnology and Pharmaceutical Engineering, National Engineering Technique Research Center for Biotechnology, Nanjing Tech University, No. 30, Puzhu South Road, Nanjing 211816, China.
Pharmaceutics
|June 26, 2026
Summary
Crystallizing the flexible antibiotic daptomycin is challenging. Researchers found that limiting its conformational diversity with specific solvents, like acetone, promotes crystallization, offering a rational screening method.
Area of Science:
- Chemical Engineering
- Crystallization Science
- Pharmaceutical Sciences
Background:
- Daptomycin, a critical lipopeptide antibiotic, is difficult to crystallize due to its flexibility and complex ionization.
- Existing literature lacks reports on daptomycin single crystals or highly crystalline powders.
- Understanding daptomycin's solubility and crystallization mechanisms is crucial for developing rational screening pathways.
Purpose of the Study:
- To elucidate the thermodynamic and kinetic factors governing daptomycin solubility and crystallization.
- To establish a rational, reduced-trial-and-error pathway for daptomycin crystallization.
Main Methods:
- Systematic measurement of daptomycin solubility in eight pure solvents using a static gravimetric method.
- Integration of experimental data with Conductor-like Screening Model for Real Solvents (COSMO-RS) and molecular dynamics (MD) simulations.
- Analysis of solvent effects on daptomycin conformational diversity and stability.
Main Results:
- Solubility trends correlated with solvent electrostatic and hydrogen-bonding properties.
- Molecular dynamics simulations identified the number of dominant conformational clusters as the key crystallization factor.
- Acetone yielded crystalline powders by restricting daptomycin conformers (12 clusters), while methanol produced amorphous precipitates (53 clusters).
Conclusions:
- The 'number of conformational clusters' effectively predicts crystallization solvent performance, bridging thermodynamics and kinetics.
- This descriptor enables rapid screening of crystallization solvents for complex, flexible molecules.
- The study provides a rational framework for crystallizing challenging macromolecules, moving beyond traditional trial-and-error methods.
