title: Characterization of Aβ Monomers through the Convergence of Ensemble Properties among Simulations with Multiple Force Fields.
abstract: Amyloid β (Aβ) monomers represent a base state in the pathways of aggregation that result in the fibrils and oligomers implicated in the pathogenesis of Alzheimer's disease (AD). The structural properties of these intrinsically disordered peptides remain unclear despite extensive experimental and computational investigations. Further, there are mutations within Aβ that change the way the peptide aggregates and are known to cause familial AD (FAD). Here, we analyze the ensembles of different isoforms (Aβ42 and Aβ40) and mutants (E22Δ, D23N, E22K, E22G, and A2T in Aβ40) of Aβ generated with all-atom replica exchange molecular dynamics (REMD) simulations on the μs/replica time scale. These were run using three different force field/water model combinations: OPLS-AA/L and TIP3P ("OPLS"), AMBER99sb-ILDN and TIP4P-Ew ("ILDN"), as well as CHARMM22* and TIP3SP ("CHARMM"). Despite fundamental changes in simulation parameters, we find that the resulting ensembles demonstrate a strong convergence in structural properties. In particular, antiparallel contacts between L17-A21 and A30-L34 are prevalent in ensembles of Aβ40, directly forming β sheets in the OPLS and ILDN combinations. A21-A30 commonly forms an interceding region that rarely interacts with the rest of the peptide. Further, Aβ42 contributes new β hairpin motifs involving V40-I41 in both OPLS and ILDN. However, the structural flexibility of the central region and the electrostatic interactions that characterize it are notably different between the different conditions. Further, for OPLS, each of the FAD mutations disrupts central bend character and increases the polymorphism of antiparallel contacts across the central region. However, the studied mutations in the ILDN set primarily encourage more global contacts involving the N-terminus and the central region, and promote the formation of new β topologies that may seed different aggregates involved in disease phenotypes. These differences aside, the large degree of agreement between simulation sets across multiple force fields provides a generalizable characterization of Aβ that is also consistent with experimental data and models.
authors.affiliation: Department of Biology, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.|Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rosenman
authors.affiliation: Department of Biology, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.|Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.|Graduate Program in Biochemistry and Biophysics, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biology, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.|Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.|Department of Physics, Applied Physics and Astronomy, Rensselaer Polytechnic Institute , 110 Eighth Street, Troy, New York 12180, United States.|Center for Non Linear Studies, Los Alamos National Laboratory , Los Alamos, New Mexico 87545, United States.
authors.forename: Angel E
authors.initials: AE
authors.lastname: García
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry*; D017433:Protein Structure, Secondary; D055672:Static Electricity
chemical_list: D016229:Amyloid beta-Peptides; D020033:Protein Isoforms