Deciphering the full-length PrPC(23-231) Receptor and Characterizing the Size/Subphase-Dependent Impact of Aβ Oligomers on the PrPC(23-231) Receptor: Insights from Molecular Dynamics Simulations

Abstract

As one of the cell surface receptors, cellular prion protein (PrPC) can bind Aβ oligomers (AβOs) and attenuate its neurotoxicity. However, there is still considerable controversy regarding the PrPC-AβO interaction, due to the polymorphism and varying size of the AβO species and void of full-length PrPC 3D structure. To solve the problem, we first complemented the missing residues in the residue-lacking crystal structure of PrPC and determine a 3D full-length PrPC receptor using “Alphafold2”. We subsequently investigated the complexes formed between the PrPC receptors—both the full-length and those missing the N-terminus—and a variety of Aβ42 species, including Aβ42 monomers, Aβ oligomers (AβOs) of varying sizes across two phases, as well as Aβ42 fibrils (AβFs), using molecular dynamics simulations. The simulated results indicate that the full-length PrPC receptor (23-231) employs a cavity, formed by its amino acid residues 44-51 and AA 95-110 regions, for Aβ42 binding. In contrast, the crystal structure of the PrPC receptor, typically lacking the N-terminal sequence (amino acids 23-87), provides a binding cavity composed of amino acids 95-110 and the C-terminal residues 131-161 to bind Aβ42, which is consistent with the diverse experimental outcomes observed (Nature 2009, 457(7233), 1128-1132; J. Am. Chem. Soc. 2022, 144(21), 9264-9270). This underscores the necessity of the novel full-length PrPC (PrPC23-231) 3D model for replicating experimental findings accurately. Additionally, we utilized both the full-length and truncated models of the PrPC receptor to clarify its disruptive effects on the growth of Aβ42 secondary nuclei structures (AβF) and its inhibitory impact on the disordered AβOs across two phases. This work provides molecular-level insights into the PrP-Aβ interaction, facilitating model selection for future experimental studies and identifying molecular targets for designing drugs intended to alleviate the toxicity of Aβ42 oligomers towards the PrPC receptor.