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Molecular Mechanism of Precision Polymers as Novel Inhibitors of Beta-Amyloid Fibril Formation

Jeffery S. Moore, University of Illinois at Urbana-Champaign

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Jeffery S. Moore, Archit Vasan, Giuseppe Leonardo Licari, Soumyo Sen

Protein aggregation is responsible for many age-related deposition diseases.  Among these, Alzheimer’s disease (AD) has been correlated with the formation of ß-amyloid (Aß) fibrils. Newly synthesized “precision polymers” in our lab have revealed a high inhibition activity against fibril formation with an unexpected dependence on polymer molecular weight. These compounds differ from our previous multivalent polymer-peptide conjugates (mPPCs) by the introduction of precisely controlled spacing between the active peptides, which offers many advantages in the drug-design phase.

To investigate the effect of spatial control and the mechanistic details of oligomerization inhibition and fibril disassembly, we propose to perform all-atom molecular dynamics (MD) simulations of these precision polymers with and without Aß oligomers.  The proposed simulations will shed light on the structural features of the precision polymers and their interaction with amyloid aggregates and will inspire the design of more active inhibitors by identifying binding sites and key intermolecular interactions.

Using our 2019 Blue Waters allocation, we were able to build and simulate a full periodic Aß fibril of 2 million atoms in size for hundreds of nanoseconds. These simulations provided a ready-to-use fibril model to test novel inhibitors and will be employed here to study the effect of the precision polymers. In this project, temperature replica exchange MD (T-REMD) will be adopted as an efficient sampling technique to explore the conformational space of these complex molecular systems.