title: Computational Methods for Structural and Functional Studies of Alzheimer's Amyloid Ion Channels.
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.
authors.affiliation: 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. jangh2@mail.nih.gov.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Bioengineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.|Department of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Fernando Teran
authors.initials: FT
authors.lastname: Arce
authors.affiliation: Department of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Joon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Gillman
authors.affiliation: Department of Bioengineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.|Department of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Department of Psychiatry, David Geffen School of Medicine, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, 90024, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Kagan
authors.affiliation: Department of Bioengineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.|Department of Mechanical and Aerospace Engineering, Materials Science Program, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Ratnesh
authors.initials: R
authors.lastname: Lal
authors.affiliation: 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. nussinor@helix.nih.gov.|Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel. nussinor@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D007473:Ion Channels; D010446:Peptide Fragments
keywords: Amyloid channel; CHARMM; Lipid bilayer; Molecular dynamics simulations; NAMD; β-Sheet channel