Fragment-based quantum mechanical parameterization of glycopeptide antibiotics for molecular simulations

Glycopeptide antibiotics such as dalbavancin and teicoplanin possess complex structures featuring modified amino acids and non-standard sugars, posing challenges for molecular simulations. We employed a fragment-based approach combined with quantum mechanical electrostatic potential calculations and RESP charge fitting to develop reliable force field parameters, especially atomic partial charges. Structural fragments were generated and subjected to ESP calculations at the HF/6-31+G(d) level using GAMESS, enabling derivation of conformation-independent atomic charges. These were integrated into the AMBER force field framework, facilitating stable energy minimizations and ready models for molecular simulations. To validate the developed parameters, the antibiotics were complexed with a peptidoglycan-mimetic pentapeptide and subjected to equilibration and short-term molecular dynamics (MD) in explicit solvent. The stability of the resulting trajectories and maintained binding interactions confirm the structural integrity and reliability of the constructed models. Our methodology extends force field applicability to structurally complex glycopeptides, supporting computational investigations of antibiotic mechanisms and design.