TY - JOUR
T1 - Binding free energy of several sterols to the N-terminal domain of Niemann-Pick C1-like 1 protein due to mutation
T2 - Molecular dynamics study
AU - Yoon, Hye Jin
AU - Lee, Yeeun
AU - Jeong, Jian
AU - Jang, Soonmin
AU - Lee, Hyung Ho
AU - Kim, Gap Sue
N1 - Publisher Copyright:
© 2022 Chemical Society Located in Taipei and Wiley-VCH GmbH.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - cholesterol transport
KW - molecular docking
KW - molecular dynamics simulation
KW - Niemann-pick disease type C (NPC) disease
UR - http://www.scopus.com/inward/record.url?scp=85139029798&partnerID=8YFLogxK
U2 - 10.1002/jccs.202200315
DO - 10.1002/jccs.202200315
M3 - Article
AN - SCOPUS:85139029798
SN - 0009-4536
VL - 70
SP - 539
EP - 546
JO - Journal of the Chinese Chemical Society
JF - Journal of the Chinese Chemical Society
IS - 3
ER -