title: Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.
abstract: Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ) peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, New York 10598, United States of America.
authors.forename: Payel
authors.initials: P
authors.lastname: Das
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, New York 10598, United States of America.
authors.forename: Seung-gu
authors.initials: SG
authors.lastname: Kang
authors.affiliation: Neural Stem Cell Institute, Rensselaer, New York 12144, United States of America.
authors.forename: Sally
authors.initials: S
authors.lastname: Temple
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, United States of America.
authors.forename: Georges
authors.initials: G
authors.lastname: Belfort
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009113:Muramidase / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D038203:alpha-Crystallin B Chain / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D038203:alpha-Crystallin B Chain; D009113:Muramidase