Molecular Dynamics Simulations of Glycosaminoglycan Oligosaccharide Using Newer Force Fields

Abstract

Heparin/heparan sulfate (H/HS) are ubiquitous biopolymers that interact with many proteins to induce myriad biological functions. It is critical to understand conformational properties of H/HS in solution so as to identify their preferred protein targets. Unfortunately, the massive heterogeneity of H/HS precludes the use of solution-based experimental techniques for the thousands of sequences that occur in nature. Computational simulations offer an attractive alternative and several all-atom force fields have been developed to understand their conformational properties. Recently, CHARMM36 carrying parameters for N-sulfamate was developed. This work compares molecular dynamics simulations of a hexasaccharide (HS06) using two all-atom force fields - CHARMM36 and GLYCAM06. We also introduce two new straightforward parameters, including end-to-end distance and minimum volume enclosing ellipsoid, to understand the conformational behavior of HS06. In addition, we analyzed inter- and intra-molecular hydrogen bonds and intermediate water bridges formed for HS06 using both force fields. Overall, CHARMM36 and GLYCAM06 gave comparable results, despite few, small differences. The MD simulations show that HS06 samples a range of conformations in solution with more than one nearly equivalent global minima, which contrasts with the assumed single conformation conclusion derived on the basis of 1HPN structure. A key reason for the stability of multiple low energy conformations was the contribution of intermediate water bridges, which is usually not evaluated in most MD studies of H/HS.