Paper Citing NAMD - Abstract
Pan, Lurong; Patterson, James C.
Molecular Dynamics Study of Zn(A beta) and Zn(A beta)(2)
PLOS ONE, 8 Art. No. e70681, SEP 27 2013
The aggregation of A beta-peptide (A beta) is widely considered to be the critical step in the pathology of Alzheimer's disease. Small, soluble A beta oligomers have been shown to be more neurotoxic than large, insoluble aggregates and fibrils. Recent studies suggest that biometal ions, including Zn(II), may play an important role in the aggregation process. Experimentally determining the details of the binding process is complicated by the kinetic lability of zinc. To study the dynamic nature of the zinc-bound A beta complexes and the potential mechanisms by which Zn(II) affects A beta oligomerization we have performed atomistic molecular dynamics (MD) simulations of Zn(A beta) and Zn(A beta)(2). The models were based on NMR data and predicted coordination environments from previous density functional theory calculations. When modeled as 4-coordinate covalently bound Zn(A beta)(n) complexes (where n = 1 or 2), zinc imposes conformational changes in the surrounding A beta residues. Moreover, zinc reduces the helix content and increases the random coil content of the full peptide. Although zinc binds at the N-terminus of A beta, beta-sheet formation is observed exclusively at the C-terminus in the Zn(A beta) and most of the Zn(A beta)(2) complexes. Furthermore, initial binding to zinc promotes the formation of intra-chain salt-bridges, while subsequent dissociation promotes the formation of inter-chain salt-bridges. These results suggest that Zn-binding to A beta accelerates the aggregation of A beta by unfolding the helical structure in A beta peptide and stabilizing the formation of vital salt-bridges within and between A beta peptides.
