Brain deposition of A beta in the form of amyloid plaques is a pathological hallmark of Alzheimer's disease. There are two major species of A beta in the brain: A beta 42 and A beta 40. Although A beta 40 is several-fold more abundant than A beta 42 in soluble form, A beta 42 is the major component of amyloid plaques. Structural knowledge of A beta 42 fibrils is important both for understanding the process of A beta aggregation and for designing fibril targeting drugs. Here we report site-specific structural information of A beta 42 fibrils at 22 residue positions based on electron paramagnetic resonance data. In combination with structure prediction program Rosetta, we modeled A beta 42 fibril structure at atomic resolution. Our A beta 42 fibril model consists of four parallel in-register beta-sheets: beta(N) (residues similar to 7-13), beta(1) (residues similar to 17-20), beta(2) (residues similar to 32-36), and beta(c) (residues 39-41). The region of beta(1)-loop-beta(2) in A beta 42 fibrils adopts similar structure as that in A beta 40 fibrils. This is consistent with our cross seeding data that A beta 42 fibril seeds shortened the lag phase of A beta 40 fibrillization. On the other hand, A beta 42 fibrils contain a C-terminal beta-arc-beta motif with a special turn, termed "arc", at residues 37-38, which is absent in A beta 40 fibrils. Our results can explain both the higher aggregation propensity of A beta 42 and the importance of A beta 42 to A beta 40 ratio in the pathogenesis of Alzheimer's disease. (C) 2016 Elsevier Inc. All rights reserved.