Development and study of computational models of low-density lipoprotein in

報告時間：2025-6-20
報告地點：Room 407
指導老師：Kun-Yi Hsin
學生：Luu Khai Nhien
摘要

Chicken embryos rely on lipids as their primary energy source during development, requiring efficient lipid transport into the egg yolk. This process involves specialized very-low-density lipoproteins targeting the yolk (VLDLy), comprising a neutral lipid core, apolipoprotein B-100 (apoB100), and apolipoprotein-VLDL-II (apoVLDL-II), with the latter being exclusively present in VLDLy. With apoVLDL-II incorporated, VLDLy particles turn significantly smaller compared with plasma VLDL (27.9 nm vs. 72.3 nm), despite the similarity between their structural components. In circulation, VLDL is metabolized into low-density lipoprotein (LDL), which diameter (19–25 nm) is comparable to VLDLy (25–44 nm), suggesting a similar structure for the non-exchangeable apoB100. Due to their seriousness in cardiovascular diseases, human LDL and apoB100 has been extensively researched. Due to the difficulty in determining the structure of human apoB100, its preliminary computational model was presented recently. This study aims to simulate the chicken LDL and apoB100 using human models as templates, as a first step to understanding VLDLy in laying hens. The LDL lipid core, comprising POPC, lysoPC, cholesterol, cholesteryl oleates, and trioleates was constructed using coarse-grained molecular dynamics simulation method. After a 1.3 microseconds simulation, the lipid core was structurally stabilized with an average pressure of 2.46 bar and a temperature of 310.01 Kelvin. As for the apoB100 moiety, a series of homology modeling and neural network methods were experimented with. Between the human and chicken apoB100, sequence alignment using BLAST showed a 50.52% overall identity and 55.82% residue similarity. Secondary structure analysis (PSIPRED) showed high similarity percentage for α-helix (31.43 and 31.74, respectively), β-strand (33.95 and 33.02, respectively), and coil (34.63 and 35.24, respectively). These results suggest that human apoB100 is suitable as a template for modeling chicken apoB100. Homology modeling with MODELLER and deep learning predictions with AlphaFold2 (AF2) produced more accurate structures compared to other software, with Ramachandran favored region score of 93.4% and 90.1%, and only 0.3% and 0.4% in the disallowed region (MODELLER and AlphaFold2, respectively). The RMSD of N-terminal domain was 1.393 and 7.240 Å in MODELLER and AF2 models compared to human apoB100. AF2 also predicted the structure of the unsolved model of apoVLDL-II with moderate accuracy (70% structure with pLDDT > 70).  A preliminary LDL model containing a lipid core and apoB100 for chickens was constructed using computational methods. This model lays the foundation for future simulations of chicken VLDL and VLDLy, providing insights into interactions among VLDL, apoB100, and apoVLDL-II in laying hens.

Keywords: Chicken embryos, computational model, low-density lipoprotein
參考文獻
  • Abraham, M. J., T. Murtola, R. Schulz, S. Páll, J. C. Smith, B. Hess, and E. Lindahl. 2015. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 1-2:19–25.
  • Berndsen, Z. T., and C. K. Cassidy. 2024. The structure of apolipoprotein B100 from human low-density lipoprotein. Nature.
  • Boyle-Roden, E., and R. L. Walzem. 2005. Integral apolipoproteins increase surface-located triacylglycerol in intact native apoB-100-containing lipoproteins. Journal of Lipid Research. 46:1624–1632.
  • Feingold, K. R. 2022. Lipid and Lipoprotein Metabolism. Endocrinology and Metabolism Clinics of North America. 51:437–458.
  • Jeiran, K., S. M. Gordon, D. O. Sviridov, A. M. Aponte, A. Haymond, G. Piszczek, D. Lucero, E. B. Neufeld, I. I. Vaisman, L. Liotta, A. Baranova, and A. T. Remaley. 2022. A New Structural Model of Apolipoprotein B100 Based on Computational Modeling and Cross Linking. International Journal of Molecular Sciences. 23:11480.
  • Jumper, J., R. Evans, A. Pritzel, T. Green, M. Figurnov, O. Ronneberger, K. Tunyasuvunakool, R. Bates, A. Žídek, A. Potapenko, A. Bridgland, C. Meyer, S. A. A. Kohl, A. J. Ballard, A. Cowie, B. Romera-Paredes, S. Nikolov, R. Jain, J. Adler, and T. Back. 2021. Highly Accurate Protein Structure Prediction with Alphafold. Nature. 596:583–589.
  • McGuffin, L. J., K. Bryson, and D. T. Jones. 2000. The PSIPRED protein structure prediction server. Bioinformatics. 16:404–405.
  • Murtola, T., T. A. Vuorela, M. T. Hyvönen, S.-J. Marrink, M. Karttunen, and I. Vattulainen. 2011. Low density lipoprotein: structure, dynamics, and interactions of apoB-100 with lipids. Soft Matter. 7:8135.
  • Perry, M. M., H. D. Griffin, and A. B. Gilbert. 1984. The binding of very low density and low density lipoproteins to the plasma membrane of the hen’s oocyte. Experimental Cell Research. 151:433–446.
  • Pettersen, E. F., T. D. Goddard, C. C. Huang, G. S. Couch, D. M. Greenblatt, E. C. Meng, and T. E. Ferrin. 2004. UCSF Chimera--a visualization system for exploratory research and analysis. Journal of Computational Chemistry. 25:1605–1612.
  • Reimund, M., A. D. Dearborn, G. Graziano, H. Lei, and J. Marcotrigiano. 2024. Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor. Nature. 1–7.
  • Robert, X., and P. Gouet. 2014. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Research. 42:W320–W324.
    Šali, A., and T. L. Blundell. 1993. Comparative Protein Modelling by Satisfaction of Spatial Restraints. Journal of Molecular Biology. 234:779–815.
  • Schneider, W., R. Carroll, D. Severson, and J. Nimpf. 1990. Apolipoprotein VLDL-II inhibits lipolysis of triglyceride-rich lipoproteins in the laying hen. Journal of Lipid Research. 31:507–513.
  • Walzem, R. L., R. J. Hansen, D. L. Williams, and R. L. Hamilton. 1999. Estrogen Induction of VLDLy Assembly in Egg-Laying Hens. The Journal of Nutrition. 129:467S472S.