4.8 Article

The Unfolding Journey of Superoxide Dismutase 1 Barrels under Crowding: Atomistic Simulations Shed Light on Intermediate States and Their Interactions with Crowders

期刊

JOURNAL OF PHYSICAL CHEMISTRY LETTERS
卷 11, 期 10, 页码 4206-4212

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.0c00699

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资金

  1. European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [840395]
  2. People Programme (Marie Curie Actions) of the European Unions Seventh Framework Programme (FP7/2007-2013) under REA grant, through the PRESTIGE programme [PCOFUND-GA-2013-609102]
  3. GENCI [x20186818]
  4. Initiative d'Excellence program from the French State [ANR-11-LABX-0011-01]
  5. Rothschild Foundation
  6. Cluster of Excellence RESOLV [EXC 1069]
  7. Human Frontier Science Program [RGP0022/2017]
  8. German-Israeli Foundation for Scientific Research and Development [1410]
  9. International Graduate School of Neuroscience (Ruhr-University Bochum)
  10. Marie Curie Actions (MSCA) [840395] Funding Source: Marie Curie Actions (MSCA)

向作者/读者索取更多资源

The thermal stability of the superoxide dismutase 1 protein in a crowded solution is investigated by performing enhanced sampling molecular simulations. By complementing thermal unfolding experiments done close to physiological conditions (200 mg/mL), we provide evidence that the presence of the protein crowder bovine serum albumin in different packing states has only a minor, and essentially destabilizing, effect. The finding that quinary interactions counteract the pure stabilization contribution stemming from excluded volume is rationalized here by exploring the SOD1 unfolding mechanism in microscopic detail. In agreement with recent experiments, we unveil the importance of intermediate unfolded states as well as the correlation between protein conformations and local packing with the crowders. This link helps us to elucidate why certain SOD1 mutations involved in the ALS disease reverse the stability effect of the intracellular environment.

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