Abstract
MD-1 is a member of the MD-2-related lipid-recognition (ML) family, and associates with RP105, a cell-surface protein that resembles Toll-like receptor 4 (TLR4). The RP105⋅MD-1 complex has been proposed to play a role in fine-tuning the innate immune response to endotoxin such as bacterial lipopolysaccharide (LPS) via TLR4⋅MD-2, but controversy surrounds its mechanism. We have used atomically detailed simulations to reveal the structural basis for ligand binding and consequent functional dynamics of MD-1 and the RP105 complex. We rationalize reports of endogenous phospholipid binding, by showing that they prevent collapse of the malleable MD-1 fold, before refining crystallographic models and uncovering likely binding modes for LPS analogs. Subsequent binding affinity calculations reveal that endotoxin specificity arises from the entropic cost of expanding the MD-1 cavity to accommodate bulky lipid tails, and support the role of MD-1 as a "sink" that sequesters endotoxin from TLR4 and stabilizes RP105/TLR4 interactions.
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