Paper Citing NAMD - Abstract
Connelly, Laura; Jang, Hyunbum; Arce, Fernando Teran; Capone, Ricardo; Kotler, Samuel A.; Ramachandran, Srinivasan; Kagan, Bruce L.; Nussinov, Ruth; Lal, Ratnesh
Atomic Force Microscopy and MD Simulations Reveal Pore-Like Structures of All-D-Enantiomer of Alzheimer's beta-Amyloid Peptide: Relevance to the Ion Channel Mechanism of AD Pathology
JOURNAL OF PHYSICAL CHEMISTRY B, 116:1728-1735, FEB 9 2012
Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of beta-amyloid (A beta) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves A beta peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the A beta peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the A beta peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of A beta-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length A beta(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-A beta isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-A beta(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of A beta ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through A beta interaction with membrane receptors.
