Pyranose Ring Puckering Thermodynamics for Glycan Monosaccharides Associated with Vertebrate Proteins

Abstract

The conformational properties of carbohydrates can contribute to protein structure directly through covalent conjugation in the cases of glycoproteins and proteoglycans and indirectly in the case of transmembrane proteins embedded in glycolipid-containing bilayers. However, there continue to be significant challenges associated with experimental structural biology of such carbohydrate-containing systems. All-atom explicit-solvent molecular dynamics simulations provide a direct atomic resolution view of biomolecular dynamics and thermodynamics, but the accuracy of the results depends on the quality of the force field parametrization used in the simulations. A key determinant of the conformational properties of carbohydrates is ring puckering. Here, we applied extended system adaptive biasing force (eABF) all-atom explicit-solvent molecular dynamics simulations to characterize the ring puckering thermodynamics of the ten common pyranose monosaccharides found in vertebrate biology (as represented by the CHARMM carbohydrate force field). The results, along with those for idose, demonstrate that the CHARMM force field reliably models ring puckering across this diverse set of molecules, including accurately capturing the subtle balance between 4C1 and 1C4 chair conformations in the cases of iduronate and of idose. This suggests the broad applicability of the force field for accurate modeling of carbohydrate-containing vertebrate biomolecules such as glycoproteins, proteoglycans, and glycolipids.

Exploration, representation and rationalization of the conformational phase-space of N-glycans

“…Either the CHARMM36m 37, 45, 46 or the GLYCAM06j 38 force field were used for the N -glycans molecules in combination with the CHARMMmodified TIP3P water model (mTIP3P) 47 or the standard version (sTIP3P) 48 , respectively. In the case of the CHARMM36m force field, the recent correction to a previous faulty implementation affecting in particular the ring inversion properties of Neu5Ac has been applied in all simulations 49 . The leap-frog algorithm was used as an integrator with a 2 fs time step and the LINCS algorithm 50 was employed to constrain bonds connected to hydrogen atoms.…”

“…In the case of the CHARMM36m force field, the recent correction to a previous faulty implementation affecting in particular the ring inversion properties of Neu5Ac has been applied in all simulations 49 . The leap-frog algorithm was used as an integrator with a 2 fs time step and the LINCS algorithm 50 was employed to constrain bonds connected to hydrogen atoms.…”

Exploration, Representation, and Rationalization of the Conformational Phase Space of N-Glycans

“…This Amber force field parameter input generation for GROMACS has been available since version 3.6. In the case of the CHARMM36 force field, the recent correction to a previous faulty implementation, affecting, in particular, the ring-inversion properties of Neu5Ac, has been applied in all simulations . The leap-frog algorithm was used as an integrator with a 2 fs time step, and the LINCS algorithm was employed to constrain bonds connected to hydrogen atoms.…”

“…In the case of the CHARMM36 force field, the recent correction to a previous faulty implementation, affecting, in particular, the ring-inversion properties of Neu5Ac, has been applied in all simulations. 49 The leap-frog algorithm was used as an integrator with a 2 fs time step, and the LINCS algorithm 50 was employed to constrain bonds connected to hydrogen atoms. Temperature control was realized via velocity rescaling 51 using a time constant of 0.1 ps, setting a reference temperature of 310.15 K. The pressure was set to 1 bar with a compressibility of 4.5 × 10 −5 bar −1 and kept constant via the Parrinello-Rahman barostat with a time constant of 5 ps.…”

Assortment of Frontiers in Protein Science

“…The conformational properties of covalently attached and bilayer contained carbohydrates influencing the structure of proteins were investigated by Guvench et al [ 11 ] on a theoretical level. The ring puckering thermodynamics of the most common vertebrate monosaccharides were investigated by extended system-adaptive biasing force all-atom explicit-solvent molecular dynamics simulations.…”