Journal of Biological Physics

, Volume 42, Issue 3, pp 453–476 | Cite as

Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization

  • Matjaž žganec
  • Nicholas Kruczek
  • Brigita Urbanc
Original Paper

Abstract

Amyloid β-protein (A β) assembles into oligomers that play a seminal role in Alzheimer’s disease (AD), a leading cause of dementia among the elderly. Despite undisputed importance of A β oligomers, their structure and the basis of their toxicity remain elusive. Previous experimental studies revealed that the [K16A] substitution strongly inhibits toxicity of the two predominant A β alloforms in the brain, A β40 and A β42, whereas the [K28A] substitution exerts only a moderate effect. Here, folding and oligomerization of [A16]A β40, [A28]A β40, [A16]A β42, and [A28]A β42 are examined by discrete molecular dynamics (DMD) combined with a four-bead implicit solvent force field, DMD4B-HYDRA, and compared to A β40 and A β42 oligomer formation. Our results show that both substitutions promote A β40 and A β42 oligomerization and that structural changes to oligomers are substitution- and alloform-specific. The [K28A] substitution increases solvent-accessible surface area of hydrophobic residues and the intrapeptide N-to-C terminal distance within oligomers more than the [K16A] substitution. The [K16A] substitution decreases the overall β-strand content, whereas the [K28A] substitution exerts only a modest change. Substitution-specific tertiary and quaternary structure changes indicate that the [K16A] substitution induces formation of more compact oligomers than the [K28A] substitution. If the structure-function paradigm applies to A β oligomers, then the observed substitution-specific structural changes in A β40 and A β42 oligomers are critical for understanding the structural basis of A β oligomer toxicity and correct identification of therapeutic targets against AD.

Keywords

Alzheimer’s disease Protein folding and assembly Oligomerization Oligomer structure Amyloid β-protein Structure-toxicity relationship 

Notes

Acknowledgments

This research was supported by Slovene human resources development and scholarship fund, grants 11012-37/2014 and 11012-32/2015 (M. žganec), and a bilateral grant by Slovenian Research Agency (B. Urbanc). The doctoral program of M. žganec is partially funded by the European Union. The access to Extreme Science and Engineering Discovery Environment (XSEDE) supercomputing facilities through grant TG-PHYS100030 (B. Urbanc), supported by the National Science Foundation, is kindly acknowledged.

Supplementary material

10867_2016_9417_MOESM1_ESM.pdf (814 kb)
(PDF 1.71 MB)

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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Matjaž žganec
    • 1
  • Nicholas Kruczek
    • 2
    • 3
  • Brigita Urbanc
    • 1
    • 2
  1. 1.Faculty of Mathematics and PhysicsLjubljanaSlovenia
  2. 2.Drexel UniversityPhiladelphiaUSA
  3. 3.University of Colorado at BoulderBoulderUSA

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