LAUSR

The inherent flexibility and conformational heterogeneity of carbohydrate pose a challenge for its modelling and sampling by existing classical force field. This work quantitatively assesses the quality of four popular carbohydrate force fields ( CHARMM36,GLYCAM06, OPLS-AA, GROMOS53A6CARBO_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 helical structure of amylose and its spontaneous helix-coil transition, it remains to be seen how existing force fields fare against modelling its structural transition. Towards this end, we perform multi microsecond 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 analysing 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 field predict a significant helix-coil transition in the amylose, GROMOS53A6CARBO_R and OPLS-AA majorly favour extended conformation. Markov State Model (MSM), built using the simulation trajectories, for each force field, provides a comparative quantification of the population of key macro states of amylose and elucidates underlying network of pathways of their mutual interconversion. The macro states obtained from MSM revealed that meta-stable helix-like and semi-coil intermediate conformations are more probable for CHARMM36, whereas elongated or helix-like conformations are more probable in OPLS-AA and GROMOS53A6CARBO_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 majority of α(1→ 4) glycosidic linkages preferred syn conformation, which is found to be energetically more favorable than anti. However, except for GROMOS53A6CARBO_R, all other force fields predicted non-negligible minor anti conformation. The multi-microsecond long simulations on the single-chain amylose, in combination with MSM, described here, suggest that sampling of α(1→ 4) linked oligosacharides on microsecond timescales 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 timescales simulations which might have hindered the comparison of the possibility of helix-coil exchange across different force fields on equal footing.