Academic Projects

The precise simulation of small drug-like molecules is critical to the understanding of how these molecules act within biological settings and to the design of effective therapeutic intervention. The coarse-grained (CG) molecular dynamics (MD) simulations, through the availability of the Martini force field, provide an effective tool to simulate complicated molecular systems on long timescales. This thesis shows the parametrization of the synthetic glucocorticoid Budesonide, which is primarily employed in the management of asthma and inflamed bowel diseases, using the Martini 3 force field framework. The primary aim of the project is the construction of an accurate coarse-grained model of Budesonide that retains salient structural and dynamic characteristics found in atomistic simulation. The Martini 3 force field, which provides higher resolution and parameter sets than the previous versions, is well suited for depiction of small organic molecules with varied chemistry. The procedure for the parametrization includes the projection of the Budesonide's atomistic structure onto an requisite CG topology, which is followed by systematic optimization and validation procedures. The atomistic reference model of Budesonide was created using LigParGen, which yielded topologies and OPLS-AA compatible parameters. Atomistic simulations were performed to obtain structural descriptors including radius of gyration, solvent-accessible surface area (SASA), and intramolecular distance distributions. These atomistic benchmarks were then used as references in guiding the CG model construction. Coarse-grained simulation was conducted according to the guidelines of the Martini 3 small molecule parametrization tutorial. The resolution and computational cost had to be balanced with the aim to incorporate key features of the molecules. The rigid steroid backbone and flexible side chains of budesonide demanded precise selection and coarsening of the beads. Building blocks of the Martini 3 were selected to depict each chemical substructure within the molecule, such as a polar rings, hydroxy groups, and ether links. Where the substructure was non-standard and direct coarsening was not feasible, analogs were identified on the basis of chemical similarity and polarity.

The bonded parameters, bond lengths, bond angles, and dihedrals, were optimized through an iterative approach to reproduce observed distributions found in the atomistic reference simulations. The optimization procedure involved the use of Boltzmann inversion plus visual examination of trajectory overlays to detect and adjust inaccuracies. Special care was taken to provide proper representation of the flexibility and planarity of rings and side chains. Validation of the CG model consisted of comparison between key structural descriptors from the atomistic and CG simulations in explicit solvent. The CG model was able to accurately reproduce the radius of gyration and SASA of Budesonide and the distribution of key intramolecular distances and angles. These findings established that the CG topology and bonded parameters were sufficient to obtain the essential conformational behavior of the molecule. Additionally, the transferability and generalizability of the CG model were considered. Although this thesis focused on the parametrization of Budesonide in isolation, the developed model lays the groundwork for future simulations involving complex environments such as lipid membranes or protein binding pockets. The model’s performance in such systems could further validate its applicability for studying Budesonide’s pharmacological interactions. Through the provision of an accurate CG model of Budesonide, the work aids the overall objective of extending the Martini-based simulations to applications in drug discovery and delivery.