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Disaggregation of amyloid-beta fibrils via natural metabolites using long timescale replica exchange molecular dynamics simulation studies

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Abstract

Context

Amyloid fibrils are self-assembled fibrous protein aggregates that are associated with several presently incurable diseases such as Alzheimer’s. disease that is characterized by the accumulation of amyloid fibrils in the brain, which leads to the formation of plaques and the death of brain cells. Disaggregation of amyloid fibrils is considered a promising approach to cure Alzheimer’s disease. The mechanism of amyloid fibril formation is complex and not fully understood, making it difficult to develop drugs that can target the process. Diacetonamine and cystathionine are potential lead compounds to induce disaggregation of amyloid fibrils.

Methods

In the current research, we have used long timescale molecular simulation studies and replica exchange molecular dynamics (REMD) for 1000 ns (1 μs) to examine the mechanisms by which natural metabolites can disaggregate amyloid-beta fibrils. Molecular docking was carried out using Glide and with prior protein minimization and ligand preparation. We focused on a screening a database of natural metabolites, as potential candidates for disaggregating amyloid fibrils. We used Desmond with OPLS 3e as a force field. MM-GBSA calculations were performed. Blood-brain barrier permeability, SASA, and radius of gyration parameters were calculated.

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Data availability

The protein structure is available in PDB (2M4J) https://www.rcsb.org/structure/2m4j. Compound 1 is available in the MolPort database bearing MolPort ID MolPort-003-846-107 and compound 2 bearing MolPort-001-779-724, respectively.

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Acknowledgements

The authors thank Schrodinger Inc. for providing software support for method development, conduction, and analysis. We thank the Department of Computer Science and Engineering, R V College of Engineering for providing access to NVIDIA A100 for performing MD simulation. We thank the staff at the School of Design at R V University for access to Mac systems for developing publishable quality images for the manuscript. We also thank the staff and team at the Department of Biotechnology, R V College of Engineering for the support.

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  1. Akshay Uttarkar and Vibha Rao gave equal contributions.

Authors and Affiliations

  1. Department of Biotechnology, R V College of Engineering, Mysuru Road, Kengeri, Bangalore, 560059, affiliated to Visvesvaraya Technological University, Belagavi, 590018, India

    Akshay Uttarkar, Vibha Rao, Dhrithi Bhat & Vidya Niranjan

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  1. Akshay Uttarkar
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VN was involved in ideation and conceptualization. AU was involved in methodology, analysis and finalizing manuscript VR and DH were involved in analysis, drafting the draft manuscript. All the authors have approved the final version of the manuscript.

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Correspondence to Vidya Niranjan.

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Supplementary information

ESM 1

Supplementary file 1. The cross-correlation matrix for compound 1 at various temperature profile at 300K, 302K, 308K, 318K, 322K and 350K respectively. (PDF 23736 kb)

ESM 2

Supplementary file 2. The cross-correlation matrix for compound 2 at various temperature profile at 300K, 302K, 308K, 318K, 322K and 350K respectively. (PDF 14681 kb)

ESM 3

Supplementary file 3. PCA plot for 3 modes for compound 1 at various temperature profile at 300K, 302K, 308K, 318K, 322K and 350K respectively. (PDF 473 kb)

ESM 4

Supplementary file 4. PCA plot for 3 modes for compound 2 various temperature profile at 300K, 302K, 308K, 318K, 322K and 350K respectively. (PDF 431 kb)

ESM 5

Supplementary Video 1. A video of movement of fibrils on interaction with compound 1 in graphics interchangeable format (GIF). (GIF 10775 kb)

ESM 6

Supplementary Video 2. A video of movement of fibrils on interaction with compound 2 in graphics interchangeable format (GIF). (GIF 6449 kb)

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Uttarkar, A., Rao, V., Bhat, D. et al. Disaggregation of amyloid-beta fibrils via natural metabolites using long timescale replica exchange molecular dynamics simulation studies. J Mol Model 30, 61 (2024). https://doi.org/10.1007/s00894-024-05860-0

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