<p>The
conformational flexibility of the glycosaminoglycans (GAGs) are 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 glucoronate and iduronate. These
calculations indicate that in some cases, an excess of 15 microseconds are required for adequate sampling
of ring pucker due to the high energy barriers between states. However, by
applying our recently developed msesMD simulation method (multidimensional 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 eleven monosaccharides found in GAGs;
this includes to
our knowledge the first simulation
study of sulfation effects on GalNAc 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-O-sulfation of GalNAc leads to reduced ring rigidity,
with a significant lowering in energy of the <sup>1</sup>C<sub>4</sub> ring
conformation; this observation may have implications for
understanding the structural basis of the biological function of GalNAc-containing
glycosaminoglycans such as dermatan sulfate.</p>
Efficient Construction of Free Energy Profiles of Breathing Metal–Organic Frameworks Using Advanced Molecular Dynamics Simulations
