Thermal Behavior and Local Structural Organization in Curcumin Polymorphs’ Bulk Phase: A Molecular Dynamics Simulation Analysis

Curcumin (CUR), a bioactive compound with known polymorphism, exhibits distinct conformational and thermophysical properties across its three crystalline forms. In this study, we employ molecular dynamics simulations to investigate the thermal behavior, local structural organization, and polymorph-specific stability of CUR in the bulk phase. We first evaluate four widely used classical force fields (OPLS-AA, CGENFF, GAFF2, and GROMOS) against experimental melting points, densities, and conformational preferences, identifying OPLS-AA as the most suitable one. Through targeted reparametrization of intramolecular dihedral angles based on DFT benchmarks, we significantly improve the ability of this force field to reproduce conformational distributions and melting transitions. Using the refined model, we characterize the temperature dependence of several structural observables, including local density (via Voronoi tessellation), nearest-neighbor distributions, pair interaction energies, hydrogen bonding, and molecular orientation. Our results reveal that conformational transitions, packing rearrangements, and fluctuations occur cooperatively near polymorph-specific temperatures, often beginning with disrupted π–π stacking and propagating through the lattice. Notably, cooling simulations fail to induce recrystallization, resulting in amorphous states. This comprehensive analysis highlights the critical interplay between molecular conformation, packing, and directional interactions in determining CUR’s polymorphic behavior, providing a mechanistic foundation for controlling phase transitions in flexible molecular solids.