Insights into the Effect of Cross-Linking on Ab Oligomer Formation and Structure

POSTER

Abstract

Amyloid beta-protein (Ab) is the main component of amyloid plaques thatrepresent one of the hallmarks of Alzheimer’s disease (AD). Ab forms lowmolecular weight (LMW) oligomers, which are hypothesized to trigger ADpathology. Because of their heterogeneous nature and relatively short life-times, Ab oligomers have not been crystallized to date and consequentlytheir structure has not been experimentally characterized. Covalent cross-linking of Ab oligomers combined with gel electrophoresis can be used tocharacterize oligomer size distributions of two predominant Ab alloforms,Ab40 and Ab42. A recent study reported formation of cross-linked Aboligomers that can form under physiological conditions in the presence ofcopper and hydrogen peroxide. Here, we use efficient discrete moleculardynamics (DMD) combined with the four-bead protein model and aminoacid-specific interactions (DMD4B-HYDRA approach) to examine the ef-fect of cross-linking on Ab oligomer formation. The results of our studydemonstrate that cross-linking via tyrosines facilitates self-assembly of bothalloforms, in particular that of Ab40, yet does not account for the formationof cross-linked Ab40 and Ab42 oligomers larger than trimers and tetramers,respectively. Cross-linking changes the secondary, tertiary, and quaternarystructure of Ab40 and Ab42 dimers and trimers by increasing the exposureof hydrophobic residues and facilitating formation of elongated oligomericshapes that differ from quasi-spherical globular structures observed in con- trol simulations. Our findings imply that amino acids other than tyrosineshave to be involved in cross-linking, the proposition that is currently underinvestigation.

Authors

  • Shuting Zhang

    Department of Physics, Drexel University

  • Debbie Andres

    Department of Applied Physics and Department of Physics, Columbia University, Istituto Italiano di Tecnologia, Graphene Labs, Italy, Department of Physics and Astronomy, Purdue University, Department of Electrical Engineering, Princeton University, Department of Applied Physics and Applied Mathematics, Columbia University, NJIT, New Jersey Inst of Technology, New Jersey Inst of Tech, New Jersey Institute of Technology, Center for Advanced Radiation Sources, University of Chicago, High Pressure Science and Technology Advanced Research, State University of New York at Stony Brook, Rutgers University, NIST, Brookhaven National Laboratory, University of Chicago, University of South Florida, ETH Zurich, Max Planck POSTECH/Korea Research Initiative, University of Virginia, Rutgers University - Camden, New Jersey Institute of technology, Shaanxi Normal University, Pohang Science and Technology University, Sungkyunkwan University, Northern Illinois University and Argonne National Laboratory, Beijing National Laboratory for Condensed Matter Physics , and Institute of Physics, Chinese Academy of Sciences, Rutgers U., Orsova Engineers, U.S. Naval Research Laboratory, Center for Space Science and Engineering Research, Virginia Tech, Virginia., Princeton University, NASA Goddard Space Flight Center, Villanova University, SOFIA/USRA, Jet Propulsion Laboratory, Hudson Regional Health Commision, Rutgers University, College of William & Mary, Department of Physics, Drexel University, Drexel University, Drexel Universty, University of Massachusetts Amherst, Pohang Institue of Science and Technology, Indiana University - Purdue University Indianapolis, Department of Physics, University of Maryland, Naval Research Laboratory, Towson Univ, Rice University, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, Department of Physics, Temple University, PulseTorr LLC, Department of Chemistry, West Chester University, Department of Physics, West Chester University, College of William and Mary Dept. of Physics, University of Virginia Dept. of Materials Science and Engineering, United States Naval Academy, Rutgers The State University of New Jersey, Univ of Maryland-College Park, Los Alamos National Laboratory, POSTECH, New Jersey Institute of Technology, Department of Electrical and Computer Engineering, HamSCI/ARRL, Virginia Tech, Rutgers University-Camden, University of Washington, Rutgers, The State University of New Jersey

  • Debbie Andres

    Department of Applied Physics and Department of Physics, Columbia University, Istituto Italiano di Tecnologia, Graphene Labs, Italy, Department of Physics and Astronomy, Purdue University, Department of Electrical Engineering, Princeton University, Department of Applied Physics and Applied Mathematics, Columbia University, NJIT, New Jersey Inst of Technology, New Jersey Inst of Tech, New Jersey Institute of Technology, Center for Advanced Radiation Sources, University of Chicago, High Pressure Science and Technology Advanced Research, State University of New York at Stony Brook, Rutgers University, NIST, Brookhaven National Laboratory, University of Chicago, University of South Florida, ETH Zurich, Max Planck POSTECH/Korea Research Initiative, University of Virginia, Rutgers University - Camden, New Jersey Institute of technology, Shaanxi Normal University, Pohang Science and Technology University, Sungkyunkwan University, Northern Illinois University and Argonne National Laboratory, Beijing National Laboratory for Condensed Matter Physics , and Institute of Physics, Chinese Academy of Sciences, Rutgers U., Orsova Engineers, U.S. Naval Research Laboratory, Center for Space Science and Engineering Research, Virginia Tech, Virginia., Princeton University, NASA Goddard Space Flight Center, Villanova University, SOFIA/USRA, Jet Propulsion Laboratory, Hudson Regional Health Commision, Rutgers University, College of William & Mary, Department of Physics, Drexel University, Drexel University, Drexel Universty, University of Massachusetts Amherst, Pohang Institue of Science and Technology, Indiana University - Purdue University Indianapolis, Department of Physics, University of Maryland, Naval Research Laboratory, Towson Univ, Rice University, Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, Department of Physics, Temple University, PulseTorr LLC, Department of Chemistry, West Chester University, Department of Physics, West Chester University, College of William and Mary Dept. of Physics, University of Virginia Dept. of Materials Science and Engineering, United States Naval Academy, Rutgers The State University of New Jersey, Univ of Maryland-College Park, Los Alamos National Laboratory, POSTECH, New Jersey Institute of Technology, Department of Electrical and Computer Engineering, HamSCI/ARRL, Virginia Tech, Rutgers University-Camden, University of Washington, Rutgers, The State University of New Jersey