Paper Info
Title
Ring Puckering Landscapes of Glycosaminoglycan-related Monosaccharides from Molecular Dynamics Simulations.
Abstract
The conformational flexibility of the glycosaminoglycans (GAGs) is known to be key in their binding and biological function, for example in regulating coagulation and cell growth. In this work, we employ enhanced sampling molecular dynamics simulations to probe the ring conformations of GAG-related monosaccharides, including a range of acetylated and sulfated GAG residues. We first perform unbiased MD simulations of glucose anomers and the epimers glucuronate and iduronate. These calculations indicate that in some cases, an excess of 15 mu s is required for adequate sampling of ring pucker due to the high energy barriers between states. However, by applying our recently developed msesMD simulation method (multi-dimensional swarm-enhanced sampling molecular dynamics), we were able to quantitatively and rapidly reproduce these ring pucker landscapes. From msesMD simulations, the puckering free energy profiles were then compared for 15 further monosaccharides related to GAGs; this includes to our knowledge the first simulation study of sulfation effects on beta-GaINAc ring puckering. For the force field employed, we find that in general the calculated pucker free energy profiles for sulfated sugars were similar to the corresponding unsulfated profiles. This accords with recent experimental studies suggesting that variation in ring pucker of sulfated GAG residues is primarily dictated by interactions with surrounding residues rather than by intrinsic conformational preference. As an exception to this, however, we predict that 4-0-sulfation of beta-GalNAc leads to reduced ring rigidity, with a significant lowering in energy of the C-1(4) ring conformation; this observation may have implications for understanding the structural basis of the biological function of beta-GalNAc-containing glycosaminoglycans such as dermatan sulfate.
Year
DOI
Venue
2019
10.1021/acs.jcim.9b00529
JOURNAL OF CHEMICAL INFORMATION AND MODELING
DocType
Volume
Issue
Journal
59
11
ISSN
Citations 
PageRank 
1549-9596
0
0.34
References 
Authors
0
2
Name
Order
Citations
PageRank
Irfan Alibay100.68
Richard A. Bryce282.41