Paper Citing NAMD - Abstract
Raz, Yoav; Miller, Yifat
Interactions between A beta and Mutated Tau Lead to Polymorphism and Induce Aggregation of A beta-Mutated Tau Oligomeric Complexes
PLOS ONE, 8 Art. No. UNSP e73303, AUG 12 2013
One of the main hallmarks of the fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is the accumulation of neurofibrillary tangles in the brain as an outcome of the aggregation of mutated tau protein. This process occurs due to a number of genetic mutations in the MAPT gene. One of these mutations is the Delta K280 mutation in the tau R2 repeat domain, which promotes the aggregation vis-a-vis that for the wild-type tau. Experimental studies have shown that in Alzheimer's disease A beta peptide forms aggregates both with itself and with wild-type tau. By analogy, in FTDP-17, it is likely that there are interactions between A beta and mutated tau, but the molecular mechanisms underlying such interactions remain to be elucidated. Thus, to investigate the interactions between A beta and mutated tau, we constructed fourteen Delta K280 mutated tau-A beta(17-42) oligomeric complexes. In seven of the mutated tau-A beta(17-42) oligoemric complexes the mutated tau oligomers exhibited hydrophobic interactions in their core domain, and in the other seven mutated tau-A beta(17-42) oligoemric complexes the mutated tau oligomers exhibited salt-bridge interactions in their core domain. We considered two types of interactions between mutated tau oligomers and A beta oligomers: interactions of one monomer of the A beta oligomer with one monomer of the mutated tau oligomer to form a single-layer conformation, and interactions of the entire A beta oligomer with the entire mutated tau oligomer to form a double-layer conformation. We also considered parallel arrangements of A beta trimers alternating with mutated tau trimers in a single-layer conformation. Our results demonstrate that in the interactions of A beta and mutated tau oligomers, polymorphic mutated tau-A beta(17-42) oligomeric complexes were observed, with a slight preference for the double-layer conformation. A beta trimers alternating with mutated tau trimers constituted a structurally stable confined beta-structure, albeit one that was energetically less stable than all the other constructed models.
