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Int. J. Mol. Sci. 2018, 19(9), 2623; https://doi.org/10.3390/ijms19092623

Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways

1
National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia
2
Department of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
*
Author to whom correspondence should be addressed.
Received: 16 August 2018 / Revised: 30 August 2018 / Accepted: 31 August 2018 / Published: 4 September 2018
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
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Abstract

The Niemann Pick type C (NPC) proteins, NPC1 and NPC2, are involved in the lysosomal storage disease, NPC disease. The formation of a NPC1–NPC2 protein–protein complex is believed to be necessary for the transfer of cholesterol and lipids out of the late endosomal (LE)/lysosomal (Lys) compartments. Mutations in either NPC1 or NPC2 can lead to an accumulation of cholesterol and lipids in the LE/Lys, the primary phenotype of the NPC disease. We investigated the NPC1(NTD)–NPC2 protein–protein complex computationally using two putative binding interfaces. A combination of molecular modeling and molecular dynamics simulations reveals atomic details that are responsible for interface stability. Cholesterol binding energies associated with each of the binding pockets for the two models are calculated. Analyses of the cholesterol binding in the two models support bidirectional ligand transfer when a particular interface is established. Based on the results, we propose that, depending on the location of the cholesterol ligand, a dynamical interface between the NPC2 and NPC1(NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD). View Full-Text
Keywords: Niemann-Pick type C disease; NPC1; NPC2; computations; simulations; cholesterol ligand; ligand transfer; binding free energy; interface stability; molecular dynamics; molecular modeling Niemann-Pick type C disease; NPC1; NPC2; computations; simulations; cholesterol ligand; ligand transfer; binding free energy; interface stability; molecular dynamics; molecular modeling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Hodošček, M.; Elghobashi-Meinhardt, N. Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways. Int. J. Mol. Sci. 2018, 19, 2623.

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