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Computational Methods for Structural and Functional Studies of Alzheimer’s Amyloid Ion Channels

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Protein Amyloid Aggregation

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1345))

Abstract

Aggregation can be studied by a range of methods, experimental and computational. Aggregates form in solution, across solid surfaces, and on and in the membrane, where they may assemble into unregulated leaking ion channels. Experimental probes of ion channel conformations and dynamics are challenging. Atomistic molecular dynamics (MD) simulations are capable of providing insight into structural details of amyloid ion channels in the membrane at a resolution not achievable experimentally. Since data suggest that late stage Alzheimer’s disease involves formation of toxic ion channels, MD simulations have been used aiming to gain insight into the channel shapes, morphologies, pore dimensions, conformational heterogeneity, and activity. These can be exploited for drug discovery. Here we describe computational methods to model amyloid ion channels containing the β-sheet motif at atomic scale and to calculate toxic pore activity in the membrane.

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Acknowledgements

This project has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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Authors and Affiliations

  1. Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD, 21702, USA

    Hyunbum Jang & Ruth Nussinov

  2. Department of Bioengineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA

    Fernando Teran Arce, Alan L. Gillman, Srinivasan Ramachandran & Ratnesh Lal

  3. Department of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA

    Fernando Teran Arce, Joon Lee, Srinivasan Ramachandran & Ratnesh Lal

  4. Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, 90024, USA

    Bruce L. Kagan

  5. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Ruth Nussinov

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  1. Hyunbum Jang
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Correspondence to Ruth Nussinov .

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    David Eliezer

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Jang, H. et al. (2016). Computational Methods for Structural and Functional Studies of Alzheimer’s Amyloid Ion Channels. In: Eliezer, D. (eds) Protein Amyloid Aggregation. Methods in Molecular Biology, vol 1345. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2978-8_16

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  • DOI: https://doi.org/10.1007/978-1-4939-2978-8_16

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2977-1

  • Online ISBN: 978-1-4939-2978-8

  • eBook Packages: Springer Protocols

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