Molecular dynamics simulation study on the inhibitory effects of choline‐O‐sulfate on hIAPP protofibrilation

Type 2 diabetes mellitus (T2Dm) is a neurodegenerative disease, which occurs due to the self‐association of human islet amyloid polypeptide (hIAPP), also known as human amylin. It was reported experimentally that choline‐O‐sulfate (COS), a small organic molecule having a tertiary amino group and sulfate group, can prevent the aggregation of human amylin without providing the mechanism of the action of COS in the inhibition process. In this work, we investigate the influence of COS on the full‐length hIAPP peptide by performing 500 ns classical molecular dynamics simulations. From pure water simulation (without COS), we have identified the residues 11–20 and 23–36 that mainly participate in the fibril formation, but in the presence of 1.07 M COS these residues become totally free of β‐sheet conformation. Our results also show that the sulfate oxygen of COS directly interacts with the peptide backbone, which leads to the local disruption of peptide–peptide interaction. Moreover, the presence of favorable peptide‐COS vdW interaction energy and high coordination number of COS molecules in the first solvation shell of the peptide indicates the hydrophobic solvation of the peptide residues by COS molecules, which also play a crucial role in the prevention of β‐sheet formation. Finally, from the potential of mean force (PMFs) calculations, we observe that the free energy between two peptides is more negative in the absence of COS and with increasing concentration of COS, it becomes unfavorable significantly indicating that the peptide dimer formation is most stable in pure water, which becomes less favorable in the presence of COS. © 2019 Wiley Periodicals, Inc.