Conformational Heterogeneity and Local Electronic Structure in Wild-Type and Arctic Amyloid-Β42
Year: 2026
Type: preprint
Abstract: Amyloid-𝛽 42 is a heterogeneous system, widely known as an intrinsically disordered protein, or IDP, sampling a variety of conformations. However, how ensemble redistribution affects the underlying local electronic structure remains less well understood. In this study, classical molecular dynamics simulations are combined with population-aware density functional theory and reduced active-space calculations to compare the LVFFA fragment of the wild-type and Arctic (E22G) variants. Common-space principal component analysis, clustering, and Ramachandran plot analysis depicted distinct trajectory distributions and greater conformational heterogeneity for the E22G trajectory. Population-ranked conformations representing 60.58% of WT and 54.98% of Arctic populations yielded conditional population-weighted B3LYP/def2-SVP HOMO-LUMO separations of 5.81 and 5.95 eV, respectively. The 0.14 eV Arctic–WT shift remained positive across moving-block bootstrap analyses. Fragment expansion altered frontier-orbital ordering, although the spatial character of LVFFA-associated states was preserved. CASCI tested active-space sensitivity, and matched UCCSD-VQE calculations reproduced CAS(4,4) CASCI reference energies for the reduced Hamiltonians. Together, these results demonstrate the importance of population-aware conformational sampling and model-definition sensitivity when relating heterogeneous biomolecular ensembles to quantum-chemical properties.
Source: ChemRxiv
Author: kushal patil
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221552695