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

Abstract

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 Nacetyl 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.

Ring Puckering Landscapes of Glycosaminoglycan-Related Monosaccharides from Molecular Dynamics Simulations

“…Similarly, the favored pucker state of IdoA2S appears at variance with that obtained from NMR of its methyl agylcone. For modeling the complex intra- and intermolecular physics of neutral and charged saccharide molecules in solution, it may be that moving beyond a fixed point charge force field could prove beneficial, as has been found elsewhere. , …”

Ion Pairing and Dielectric Decrement in Glycosaminoglycan Brushes

“…The role of ion pairing of the cations to specific oxygen atoms of the anionic carboxylates and sulfates in the GAGs is then presented. We show that all-atom MD simulations of hyaluronic acid brushes can produce consistent brush electroneutrality with anion exclusion using both CHARMM36 additive all-atom carbohydrate force fields and CHARMM-Drude polarizable force fields for carbohydrates. − The effect of pair-specific Lennard–Jones parameters on the Donnan potential, ion pairing, dielectric constant, and GAG brush topology was evaluated for Na + and K + interactions with the carboxylate and sulfate anions. We conclude by postulating a cation-centric mean-field model for the GAG brushes that includes electrostatic, Born-hydration, and ion-pairing energies that govern quasi-static electroneutrality.…”

CHARMM‐GUI Drude prepper for molecular dynamics simulation using the classical Drude polarizable force field

“…The detected linkage information is passed in the form of a CHARMM stream file. Note that Drude Prepper only supports the sugars that are available in the Drude FF such as general furanoses, pyranoses, hexouronic acids, and other acid moieties 88 . Additional monosaccharides and linkage types, such as seven‐, eight‐, nine‐carbon sugars, and N/O glycosidic linkages to proteins will be included as they are developed.…”