An extensive review on amyloid oligomers has recently been published in Chemical Reviews.
Below is an excerpt describing our multi-scale simulations of superoxide dismutase 1 (SOD1):
CG simulations can be directly complemented by high-resolution atomistic approaches in a multiscale strategy as recently proposed for investigating the effect of crowding on the stability of the aggregation prone SOD1 protein;(408,415) see Figure 12. Here, a large-scale lattice Boltzmann MD simulation served to identify states of local packing around SOD1 in a crowded protein solution (BSA), which was then closely examined using atomistic enhanced-sampling simulations. In line with experimental results, the presence of crowders was found to have only a minor effect on the overall thermal stability of SOD1, and crowding did not dramatically perturb the unfolding process. Nevertheless, the simulations identified a fragile region on the β barrel, susceptible to early unfolding and subsequently showing a strong propensity to interact with the crowder. This semiunfolded intermediate state, appearing to be stabilized by the interactions with the crowded environment, was hypothesized to play a role in the aggregation of SOD1 in the crowded cellular conditions.
Figure 12. Unfolding and stability of SOD1 in crowded conditions.(408,415) (A) Snapshot from a 1 μs coarse-grain LBMD simulation of loop-truncated SOD1 monomers immersed in a 200 g/L BSA solution.(408) (B) Representative states of local packing around SOD1 extracted from the coarse-grain simulation and converted into a fully all-atom representation. (C) Thermal stability—calculated using enhanced-sampling all-atom simulations—of SOD1 in the different states of local packing. The stability of the SOD1 monomer is expressed by means of the secondary-structure content of the protein. Comparison with a result obtained in dilute conditions reveals only a weak effect induced by crowding.(415) (D) Semiunfolded intermediate state observed in the enhanced-sampling all-atom simulations. The blue clouds, representing the spatial distribution of BSA atoms in contact with SOD1, show that the denaturated region has an increased probability to interact with the crowder.(415)
408 Gnutt, D.; Timr, S.; Ahlers, J.; Ko, B.; Manderfeld, E.; Heyden, M.; Sterpone, F.; Ebbinghaus, S. Stability Effect of Quinary Interactions Reversed by Single Point Mutations. J. Am. Chem. Soc. 2019, 141, 4660– 4669, DOI: 10.1021/jacs.8b13025
415 Timr, S.; Gnutt, D.; Ebbinghaus, S.; Sterpone, F. The Unfolding Journey of Superoxide Dismutase 1 Barrels under Crowding: Atomistic Simulations Shed Light on Intermediate States and Their Interactions with Crowders. J. Phys. Chem. Lett. 2020, 11, 4206– 4212, DOI: 10.1021/acs.jpclett.0c00699
Reprinted with permission from
Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis
Phuong H. Nguyen, Ayyalusamy Ramamoorthy, Bikash R. Sahoo, Jie Zheng, Peter Faller, John E. Straub, Laura Dominguez, Joan-Emma Shea, Nikolay V. Dokholyan, Alfonso De Simone, Buyong Ma, Ruth Nussinov, Saeed Najafi, Son Tung Ngo, Antoine Loquet, Mara Chiricotto, Pritam Ganguly, James McCarty, Mai Suan Li, Carol Hall, Yiming Wang, Yifat Miller, Simone Melchionna, Birgit Habenstein, Stepan Timr, Jiaxing Chen, Brianna Hnath, Birgit Strodel, Rakez Kayed, Sylvain Lesné, Guanghong Wei, Fabio Sterpone, Andrew J. Doig, and Philippe Derreumaux
Chemical Reviews 2021 121 (4), 2545-2647
Copyright 2021 American Chemical Society.