Binding free energy of several sterols to the N-terminal domain of Niemann-Pick C1-like 1 protein due to mutation: Molecular dynamics study

The membrane protein Niemann-Pick type C1-like 1 (NPC1L1) plays a central role in the absorption of cholesterol in the small intestine. Other sterols, notably vitamin E and vitamin K1 also utilize NPC1L1 as a membrane transporter even though other absorption paths exist. Many NPC1L1 mutations causing the disease due to poor transport of cholesterol are known. It is not clear at this moment if the same mutation can lead to reduced transport behavior with these vitamins. In this study, we have obtained the binding free energies of these two sterols using molecular dynamics simulation and compared these values with the cholesterol-binding free energy. The N-terminal domain (NTD) of the wild as well as the disease-causing two mutations, T61M and L110F, are used for this purpose. The result indicates that the mutations show reduced binding affinity compared to the wild except for the vitamin K1 in the T61M mutant, which has increased binding free energy. Also, we found the similarity of the key amino acids responsible for the change of free energy by mutation between T61M and L110F. At the same time, non-negligible differences exist also.