Exploring sterol transportation behavior of the Niemann-Pick C1-like 1 protein with V55L mutation: Sterol-NPC1L1 N-terminal binding energy estimation via molecular dynamics simulations

ABSTRACTThe Niemann-Pick C1-like 1 (NPC1L1) protein facilitates cholesterol absorption in the small intestine and mediates the absorption of other sterols, including vitamins E, vitamin K1, and coenzyme Q10 (CoQ10). Ezetimibe is a drug used to treat high blood cholesterol and lipid abnormalities. However, V55L/I1223N and non-conserved V55 mutations in humans and rats, respectively, have been linked to ezetimibe insensitivity. In this study, molecular modeling, which combines the molecular dynamics simulations with the molecular mechanics Poisson-Boltzmann surface area approach, was used to estimate the change in the binding free energy of the NPC1L1 N-terminal domain (NTD) owing to the V55L mutation, Further, free energy changes for the three sterols namely, vitamin E, vitamin K1, and CoQ10 were estimated. The current study found that the V55L mutation reduced the cholesterol to NPC1L1-NTD binding free energy, which compensates for the decreased cholesterol passage through the putative tunnel induced by the ezetimibe. Therefore, molecular modeling of the free energy changes owing to mutations can successfully provide insights into the intricate details of drug inhibitors.KEYWORDS: Molecular dynamics simulationmolecular dockingNiemann-pick type C (NPC) disease, cholesterol transport AcknowledgmentsThis work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government under Grant numbers 2021R1A2C1004388 to HYJ, 2022R1A2B5B02002529 and 2022R1A5A6000760 to LHH). This work was supported by the National Supercomputing Center with supercomputing resources, including technical support from KSC-2021-CRE-0253 and KSC-2022-CRE-0167 from HJY.Disclosure statementNo potential conflict of interest was reported by the authors.Author contributionsH.-J.Y., S.H.K., S.J., and H.H.L. conceived and designed the experiments. H. J. Y., E.K., and Y.L. performed the computations. All authors analyzed the data, compiled and edited the manuscript.Supplemental dataSupplemental data for this article can be accessed online at https://doi.org/10.1080/02286203.2023.2265543Additional informationFundingThe work was supported by the National Research Foundation of Korea [2022R1A2B5B02002529]; National Research Foundation of Korea [2022R1A5A6000760]; National Research Foundation of Korea [2021R1A2C1004388].Notes on contributorsHye-Jin YoonHye-Jin Yoon is a research professor. Her research area is structural biochemistry including biomolecular structure determination using X-ray crystallography.Yeeun LeeYeeun Lee is a Ph.D. candidate student after receiving a MS Degree in science. She is under the supervision of Professor S. Jang.Sun-Hong KimSun-Hong Kim is a Ph.D. candidate student under the guidance of Professor H. H. Lee.Eunae KimEunae Kim is a professor, who specializes in drug discovery and biomolecular simulation.Hyung Ho LeeHyung Ho Lee, an associate professor, specializes in membrane proteins, including receptors and channels, using X-ray crystallography and cryo-EM.Soonmin JangSoonmin Jang is a professor. As a theoretical chemist, his research includes computer simulation of biomolecules and nanomaterials.