Understanding of the detailed dietary cholesterol exchange in cellular environment still remains as an open subject. The mutation of one of NPC1 (Niemann-Pick type C1) and NPC2 (Niemann-Pick type C2), which are main players of cholesterol control in lysosome, leads to disease, called Niemann-Pick disease type C (NPC) disease. Meanwhile, the transmembrane protein NPC1L1 (Niemann-Pick type C1 like 1), which is related to the dietary cholesterol absorption process in small intestine, shares sequence homology with NPC1. However, unlike NPC1, NPC2 is not involved in cholesterol internalization with NPC1L1. The structure of NTD of NPC1 in complex with cholesterol (PDB id: 3GKH and 3GKI) was known while only cholesterol free NTD (PDB id: 3QNT) is known for NPC1L1. It is noted that the whole cryo-EM structure of NPC1 is determined (PDB id: 3JD8).
We compared the cholesterol complex of NPC1L1 and NPC1 with molecular docking followed by molecular dynamics study for better understanding of these underlying behavior. The NTD molecular dynamics simulation of NPC1 and NPC1L1 complex with cholesterol shows different structural and dynamical features. The difference in cholesterol internalization mechanism between NPC1 and NPC1L1 must be closely related to these structural and dynamical behaviors. We believe the current study can contribute understanding of cholesterol absorption/re-absorption process via NPC1 and NPC1L1 and their difference with atomic detail.