Quantitative Assessment of the Conformational Heterogeneity in Amylose across Force Fields

The inherent flexibility and conformational heterogeneity of a carbohydrate pose a challenge for its modeling and sampling by the existing classical force field. This work quantitatively assesses the quality of four popular carbohydrate force fields (CHARMM36, GLYCAM06, OPLS-AA, GROMOS53A6_{CARBO_R}) against their ability to accurately model the conformational landscape of a dodecamer of single-stranded amylose, the key constituent of starch. While past NMR and X-ray studies have hinted at evidence of a helical structure of amylose and its spontaneous helix-coil transition, it remains to be seen how existing force fields fare against modeling its structural transition. Toward this end, we perform a multimicrosecond long extensive molecular dynamics simulation of dodecamer of a single-stranded amylose chain in explicit water in each of the four force fields and assess these force fields' ability to model relative structural transitions via analyzing the radius of gyration, glycosidic linkage orientation, and pyranose ring puckering of the amylose. In particular, the simulations show that while GLYCAM06 and CHARMM36 force fields predict a significant helix-coil transition in the amylose, GROMOS53A6_{CARBO_R} and OPLS-AA majorly favor extended conformation. The Markov State Model (MSM), built using the simulation trajectories, for each force field, provides a comparative quantification of the population of key macrostates of amylose and elucidates an underlying network of pathways of their mutual interconversion. The macrostates obtained from MSM revealed that metastable helixlike and semicoil intermediate conformations are more probable for CHARMM36, whereas elongated or helixlike conformations are more probable in OPLS-AA and GROMOS53A6_{CARBO_R}. GLYCAM06 showed significant probability for both helix and coil conformations along with intermediate conformations. We find that the differences in the conformations across force fields are governed by differences in the kinetics of glycosidic linkages and pyranose ring pucker conformers. All four force fields share one common point that the majority of α(1 → 4) glycosidic linkages preferred syn conformation, which is found to be energetically more favorable than anti. However, except for GROMOS53A6_{CARBO_R}, all other force fields predicted non-negligible minor anti conformation. The multimicrosecond long simulations on the single-chain amylose, in combination with MSM, described here, suggest that sampling of α(1 → 4) linked oligosacharides on microsecond time scales enable quantitative predictions of helix-coil, glycosidic linkage, and pyranose ring exchange kinetics. These exchange kinetics have otherwise remained inaccessible to quantification by experiments or nanosecond time scale simulations which might have hindered the comparison of the possibility of helix-coil exchange across different force fields on equal footing.