Abstract
Synthetic analogues of mycobacterial trehalose-dimycolate such as trehalose acyl esters have been proposed as novel adjuvants for vaccination. They induce an immune response by binding to the macrophage C-type lectin receptor Mincle. The binding site of trehalose is known, but there is yet only very limited structural information about the binding mode of the acyl esters. Here, we performed a systematic molecular dynamics study of trehalose mono-and diesters with different chain lengths. All acyl chains investigated exhibited a high flexibility and interacted almost exclusively with a hydrophobic groove on Mincle. Despite the limited length of this hydrophobic groove, the distal parts of the longer monoesters can still form additional interactions with this surface region due to their conformational flexibility. In diesters, a certain length of the second acyl chain is required to contact the hydrophobic groove. However, a stable concomitant accommodation of both acyl chains in the groove is hampered by the conformational rigidity of Mincle. Instead, multiple dynamic interaction modes are observed, in which the second acyl chain contributes to binding. This detailed structural information is considered helpful for the future design of more affine ligands that may foster the development of novel adjuvants.
Highlights
Same length of the individual acyl chains lead to a further enhanced immune reaction[8]. It has been proposed in this context that one acyl chain of the diesters might reside within the hydrophobic groove whereas the other one could have a different binding site[12]
One method that allows to elucidate structural details of such flexible interactions, which can hardly be assessed by crystallographic analysis, are molecular dynamics (MD) simulations
In order to get insight into (i) the influence of the length of the acyl chain upon binding affinity and (ii) the difference between monoesters and diesters, we performed a series of all-atom molecular dynamics simulations of Mincle bound to different trehalose ester ligands in explicit water
Summary
Synthetic analogues of mycobacterial trehalose-dimycolate such as trehalose acyl esters have been proposed as novel adjuvants for vaccination They induce an immune response by binding to the macrophage C-type lectin receptor Mincle. Multiple dynamic interaction modes are observed, in which the second acyl chain contributes to binding This detailed structural information is considered helpful for the future design of more affine ligands that may foster the development of novel adjuvants. One method that allows to elucidate structural details of such flexible interactions, which can hardly be assessed by crystallographic analysis, are molecular dynamics (MD) simulations This method has been previously applied to investigate the binding of glucose monoesters to Mincle[11], whereas there is yet no correspondent information available for trehalose mono- and diesters. We examined trehalose-6-monoesters with acyl chains comprising 4, 8, 12, and 18 carbon
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