Drude Polarizable Force Field Parametrization of Carboxylate and N-Acetyl Amine Carbohydrate Derivatives.

In this work, we report the development of Drude polarizable force field parameters for the carboxylate and N-acetyl amine derivatives, extending the functionality of the existing Drude polarizable carbohydrate force field. The force field parameters have been developed in a hierarchical manner, reproducing the quantum mechanical gas-phase properties of small model compounds representing the key functional group in the carbohydrate derivatives, including optimization of the electrostatic and bonded parameters. The optimized parameters were then used to generate the models for carboxylate and N-acetyl amine carbohydrate derivatives. The transferred parameters were further tested and optimized to reproduce crystal geometries and J-coupling data from nuclear magnetic resonance experiments. The parameter development resulted in the incorporation of d-glucuronate, l-iduronate, N-acetyl-d-glucosamine (GlcNAc), and N-acetyl-d-galactosamine (GalNAc) sugars into the Drude polarizable force field. The parameters developed in this study were then applied to study the conformational properties of glycosaminoglycan polymer hyaluronan, composed of d-glucuronate and N-acetyl-d-glucosamine, in aqueous solution. Upon comparing the results from the additive and polarizable simulations, it was found that the inclusion of polarization improved the description of the electrostatic interactions observed in hyaluronan, resulting in enhanced conformational flexibility. The developed Drude polarizable force field parameters in conjunction with the remainder of the Drude polarizable force field parameters can be used for future studies involving carbohydrates and their conjugates in complex, heterogeneous systems.