Association Thermodynamics and Conformational Stability of β-Sheet Amyloid β(17-42) Oligomers: Effects of E22Q (Dutch) Mutation and Charge Neutralization

Abstract

Amyloid fibrils are associated with many neurodegenerative diseases. It was found that amyloidogenic oligomers, not mature fibrils, are neurotoxic agents related to these diseases. Molecular mechanisms of infectivity, pathways of aggregation, and molecular structure of these oligomers remain elusive. Here, we use all-atom molecular dynamics, molecular mechanics combined with solvation analysis by statistical-mechanical, three-dimensional molecular theory of solvation (also known as 3D-RISM-KH) in a new MM-3D-RISM-KH method to study conformational stability, and association thermodynamics of small wild-type A β 17–42 oligomers with different protonation states of Glu 22, as well the E22Q (Dutch) mutants. The association free energy of small β-sheet oligomers shows near-linear trend with the dimers being thermodynamically more stable relative to the larger constructs. The linear (within statistical uncertainty) dependence of the association free energy on complex size is a consequence of the unilateral stacking of monomers in the β-sheet oligomers. The charge reduction of the wild-type A β 17–42 oligomers upon protonation of the solvent-exposed Glu 22 at acidic conditions results in lowering the association free energy compared to the wild-type oligomers at neutral pH and the E22Q mutants. The neutralization of the peptides because of the E22Q mutation only marginally affects the association free energy, with the reduction of the direct electrostatic interactions mostly compensated by the unfavorable electrostatic solvation effects. For the wild-type oligomers at acidic conditions such compensation is not complete, and the electrostatic interactions, along with the gas-phase nonpolar energetic and the overall entropic effects, contribute to the lowering of the association free energy. The differences in the association thermodynamics between the wild-type A β 17–42 oligomers at neutral pH and the Dutch mutants, on the one hand, and the A β 17–42 oligomers with protonated Glu 22, on the other, may be explained by destabilization of the inter- and intrapeptide salt bridges between Asp 23 and Lys 28. Peculiarities in the conformational stability and the association thermodynamics for the different models of the A β 17–42 oligomers are rationalized based on the analysis of the local physical interactions and the microscopic solvation structure.