Complex System Assembly Underlies a Two-Tiered Model of Highly Delocalized Electrons

Abstract

Amyloid fibrils are exceptionally stable oligomeric structures with extensive, highly cooperative H-bonding networks whose physical origin remains elusive. While nonpolar systems benefit from both H-bonds and hydrophobic interactions, we found that highly polar sequences containing glutamine and asparagine amino acid residues form hyperpolarized H-bonds. This feature, observed by density functional theory calculations, encodes the origin of these polar oligomers' high stability. These results are explained in a theoretical model for complex amyloid assembly based on two different types of cooperative effects resulting from highly delocalized electrons, one of which is always present in both polar and hydrophobic systems. Experimental electric conductivity measurements, ThT fluorescence enhancement, and NMR spectroscopy support this proposal and reveal the conditions for disassembly.

Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling

“…This sequence variation could potentially be related to the unique turnover properties of these amyloids. Polar residues within amyloids, such as the Gln in position P2, have been suggested to promote amyloid oligomerization through hyperpolarized H-bonds between the side chains (Mompeán et al, 2016). cRHIM sequences instead contain other polar residues at P2—His or Thr in Drosophila , and even Lys in other insect species.…”

“…In addition, the sequence flanking the tetrapeptide core of the Drosophila cRHIMs, which demonstrably contributed to fibril formation, are also rich with polar residues, such as Q, N, S, and T. It is plausible that the flanking regions further contribute to the unique oligomerization and disassembly properties of the Imd fibrils. In the case of yeast Sup35 prions, disruption of these polar residue-generated H-bonds was shown to cause disassembly of the fibrils (Mompeán et al, 2016). If similar H-bonds contribute to the cRHIM amyloid formation, breaking these bonds could be one way of destabilizing the fibrils and disassembling the Imd signaling complex.…”

An Amyloid-Like Pathological Conformation of TDP-43 Is Stabilized by Hypercooperative Hydrogen Bonds

“…We have recently compared hydrogen bond cooperativity in a Q/N-rich amyloid, the paradigmatical GNNQQNY heptapeptide form the yeast prion Sup35, to the hydrophobic amyloid M 35 VGGVV 40 from Aβ (Mompeán et al, 2016b). Whereas the backbone amide groups of both Q/N-rich and hydrophobic amyloids experience stabilization due to hyperpolarization, an additional and stronger type of hyperpolarization occurs in Asn and Gln side chain amides (Figure 2B).…”

Point mutations in the N-terminal domain of transactive response DNA-binding protein 43 kDa (TDP-43) compromise its stability, dimerization, and functions

“…In early 2016, the Q/N-rich segment, or part of it, was found to be intact in TDP-43 aggregates from ex vivo brain tissue, whereas all other segments of the CTR are heavily phosphorylated, deamidated, and oxidized (17). Because the exceptionally strong hydrogen-bonding networks of Q/N-rich amyloids (18) could impede such chemical modifications, we have recently interpreted these data as supporting our amyloid-like model of the Q/N-rich segment (19).…”