Extension and validation of the GROMOS 53A6_glyc parameter set for glycoproteins

Abstract

An extension of the GROMOS 53A6GLYC force field for carbohydrates to encompass glycoprotein linkages is presented. The set includes new atomic charges and incorporates adequate torsional potential parameters for N-, S-, C-, P-, and O-glycosydic linkages, offering compatibility with the GROMOS force field family for proteins. Validation included the description of glycosydic linkage geometries between amino acid and monosaccharide residues, comparison of NMR-derived protein-carbohydrate and carbohydrate-carbohydrate nuclear overhauser effect (NOE) signals for glycoproteins and the effects of glycosylation on protein flexibility and dynamics.

Conformational stability of the epidermal growth factor (EGF) receptor as influenced by glycosylation, dimerization and EGF hormone binding

“…Protein N‐glycosylation showed a more significant impact, especially when the protein was in its dimeric form. This finding confirms the importance of N‐linked glycans in stabilizing protein conformation, and aligns with the mechanistic model that binding of EGF is associated with a dramatic conformational change …”

“…The two sugar molecules in ASN3 have a beta 1 → 4 connection. The employed parameters were compiled based on previously validated GROMOS potential‐energy and interaction terms, in which the monosaccharides were described as in GROMOS 45A4 parameters set, and the N‐glycosydic linkage as in GROMOS 53A6glyc force field . Subsequently, the EGFR PDB ID 1IVO structure was modified to prepare the simulated systems to be a monomer or a dimer, glycosylated or nonglycosylated, and with or without its natural binding ligand (EGF).…”

“…Several studies have shown that N‐linked glycosylation of the ErbB proteins is an important factor in regulating their dimerization and function . In addition, previous molecular dynamics simulations of N‐linked glycans have shown for a number of systems that glycosylation confers stability to the glycoprotein to which they are attached . Although complete processing of EGFR glycans to higher order mannose‐type or complex‐type oligosaccharides is not essential for protein function, the presence of simple glycans, such as mono‐ or disaccharides, were observed to help provide more stable configurations.…”

“…[10][11][12][13][14][15] In addition, previous molecular dynamics simulations of N-linked glycans have shown for a number of systems that glycosylation confers stability to the glycoprotein to which they are attached. [16][17][18] Although complete processing of EGFR glycans to higher order mannose-type or complex-type oligosaccharides is not essential for protein function, 19 the presence of simple glycans, such as mono-or disaccharides, were observed to help provide more stable configurations. Based on this observation, Takahashi et al have postulated that N-glycans affect the conformation of ErbB family, which is crucial for their natural activity.…”

Recent Advances in NMR Studies of Carbohydrates

“…Recent developed GLY-CAM06 [162], CHARMM36 [163], GROMOS 53A6 GLYC [164], and OPLS-AA-SEI (scaling electrostatic interaction) [165] force fields are well defined for the conformational prediction of carbohydrates. Nowadays, modern carbohydrate force fields allowed to predicted the most important set of parameters of the structure of carbohydrates.…”