Solvent Model Benchmark for Molecular Dynamics of Glycosaminoglycans

Abstract

In computational studies of glycosaminoglycans (GAGs), a group of anionic, periodic linear polysaccharides, so far there has been very little discussion about the role of solvent models in the molecular dynamics simulations of these molecules. Predominantly, the TIP3P water model is commonly used as one of the most popular explicit water models in general. However, there are numerous alternative explicit and implicit water models that are neglected in the computational research of GAGs. Since solvent-mediated interactions are particularly important for GAG dynamic and structural properties, it would be of great interest for the GAG community to establish the solvent model that is suited the best in terms of the quality of theoretically obtained GAG parameters and, at the same time, would be reasonably demanding in terms of computational resources required. In this study, heparin (HP) was simulated using five implicit and six explicit solvent models with the aim to find out how different solvent models influence HP's molecular descriptors in the molecular dynamics simulations. Here, we initiate the search for the most appropriate solvent representation for GAG systems and we hope to encourage other groups to contribute to this highly relevant subject.

Interplay of heparan sulfate chains with the core proteins of syndecans 2 and 4

“…This might be due to the formation of intramolecular hydrogen bonds involving sulfate groups, 33 and to the presence of the counterions added for the simulations, which bind to the GAG chain and mask its charges. 34 The amino acid sequences located between the GAGosylation sites were not extended when HS chains were attached to the core proteins (Figures 1 and 2).…”

“…In most simulations of the GAGosylated syndecans 2 and 4, all three HS chains did not interact with the core proteins at the same time, and repelled each other due to their negative charges However, one HS chain adopted a compact conformation in the first simulation of syndecan‐2, and in the first, second and fifth simulations of syndecan‐4 (Figure 2). This might be due to the formation of intramolecular hydrogen bonds involving sulfate groups, 33 and to the presence of the counterions added for the simulations, which bind to the GAG chain and mask its charges 34 . The amino acid sequences located between the GAGosylation sites were not extended when HS chains were attached to the core proteins (Figures 1 and 2).…”

Extension of the SUGRES-1P Coarse-Grained Model of Polysaccharides to Heparin

“…The initial parameters used in the effective energy terms were determined based on all-atom MD simulations of HP using the GLYCAM06 force field and the TIP3P explicit water model . However, the limitations of different water models in all-atom simulations of GAGs have been demonstrated in some studies: TIP3P may not reproduce the charge distribution with the same quality as more complex solvent models and therefore result in highly bent conformations of HP and other GAGs. , This is likely caused by the accumulation of counterions near the GAG molecules, which enabled the relatively close contacts between sugar residues. Therefore, the tendency of HP to adopt coiled and bent conformations when simulated in the CG SUGRES-1P force field may be influenced by the origin of the parameters of the force field used to obtain them …”

Glycan Shape, Motions, and Interactions Explored by NMR Spectroscopy

“…Even though sampling of conformational space by MD simulations using the Drude model is ∼4-fold slower than the additive CHARMM force field, and ∼8-fold slower than using a hydrogen mass repartitioning (HMR) approach by increasing the mass of hydrogen by distributing a heavy atom mass to hydrogen atom(s) attached to the heavy atom, the modeling is performed in a more realistic way, for glycans per se but in particular for understanding and unveiling the structural basis of ligand recognition and specificity in carbohydrate–protein interactions, which calls for further developments of the Drude polarizable force fields. Moreover, the choice of water model for MD simulations may be crucial for the outcome and the resulting conclusions that can be made, − and so can the absence or presence of small partial atomic charges on aliphatic protons of rhamnosyl residues be in modeling of polysaccharides …”