Thermodynamics and structural description of Amyloid-beta 1-42 and pyroglutamate-modified Amyloid-beta 3-42 peptides binding to fibrils.
Biochemistry
Final Report Abstract
We have investigated the structure and thermodynamics of interaction between Aβ42 as well as pE-Aβ(3-42) monomers and Aβ42 fibrils. This project was a close experimental and computational collaboration aimed at calculating binding affinities of Aβ peptides when interacting with Aβ fibrils with both methods and provide important insights into the fibril assembly process at atomistic resolution. We have first studied the stability of Aβ42 and pE-Aβ(3-42) monomers using Hamiltonian replica exchange MD (H-REMD) simulations and we observed significant differences between the two peptides at structural level. Overall, the pE-Aβ(3-42) monomer displayed more hydrophobic amino acids exposed to the solvent and increased amounts of β-sheet and helix secondary structure, which could explain its stronger attachment to fibrils observed in experiments. Moreover, for the Aβ42 monomer we have identified a novel structural conformation which has many similarities with peptides from the fibril structure. Using the most stable monomer conformations from the previous step we have then investigated the attachment of Aβ42 and pE-Aβ(3-42) monomers to Aβ42 fibrils by means of long H-REMD simulations. Due to the strong binding between the peptides and the fibrils, the binding affinities were further calculated by using the umbrella sampling method. Experimental binding affinities were also calculated experimentally, using the Surface Plasmon Resonance method, which corroborated the computational results. Here, we observed different binding modes for the two alloforms when interacting with Aβ42 fibrils and overall a stronger binding for the pE-Aβ(3-42) monomer. One of the main milestones which was not achieved in this project was the study of the monomer binding to the fibril end. This was due to the unstable nature of the peptides at the fibril end. We have performed a large number of simulations where we tested different force fields and protocols for the stability of the fibril end, however without success. Finally, we also investigated the interaction of Aβ42 monomers with D-peptides which are promising drug candidates in the fight against the Alzheimer’s Disease. By using long H- REMD simulations we calculated binding affinities, enthalpies and entropies which are in good agreement with experimental observations. We further elucidated key structural interactions which contribute to the diverse binding modes between the two interacting biomolecules. In conclusion, we have successfully completed the majority of the project goals and contributed to the scientific advance by publishing two peer-reviewed manuscripts, one pre-print, a doctoral and a masters theses, as well as two more manuscripts in preparation to be submitted. There are still some scientific questions to be addressed by the computational methods, especially in regard to the fibril growth by monomer addition.
Publications
- Monomeric amyloid β-peptide (1-42) significantly populates compact fibril-like conformations, BioRxiv
Barz B., Buell A. K. and Nath S.
(See online at https://doi.org/10.1101/2020.06.23.156620) - Compact fibril-like structure of amyloid β-peptide (1–42) monomers, Chemical Communications, 57, 947-950, 2021
Barz B., Buell A. K., and Nath S.
(See online at https://doi.org/10.1039/D0CC06607A) - Ineraction of Therapeutic d-Peptides with Aβ42 Monomers, Thermodynamics, and Binding Analysis, ACS Chemical Neuroscience, 13, 11, 1638–1650, 2022
Leguizamon Herrera V. L., Buell A. K., Willbold D., and Barz B.
(See online at https://doi.org/10.1021/acschemneuro.2c00102)
