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Protein Amyloid Aggregation

Volume 1345 of the series Methods in Molecular Biology pp 251-268

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

  • Hyunbum JangAffiliated withCancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick
  • , Fernando Teran ArceAffiliated withDepartment of Bioengineering, Materials Science Program, University of California, San DiegoDepartment of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego
  • , Joon LeeAffiliated withDepartment of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego
  • , Alan L. GillmanAffiliated withDepartment of Bioengineering, Materials Science Program, University of California, San Diego
  • , Srinivasan RamachandranAffiliated withDepartment of Bioengineering, Materials Science Program, University of California, San DiegoDepartment of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego
  • , Bruce L. KaganAffiliated withDepartment of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California
  • , Ratnesh LalAffiliated withDepartment of Bioengineering, Materials Science Program, University of California, San DiegoDepartment of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego
  • , Ruth NussinovAffiliated withCancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at FrederickDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University Email author 

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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.

Key words

Amyloid channel β-Sheet channel Lipid bilayer Molecular dynamics simulations CHARMM NAMD