Conformational Heterogeneity and Local Electronic Structure in Wild-Type and Arctic Amyloid-Β42
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.
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BibTeX
@misc{patil2026conformational,
title = {{Conformational Heterogeneity and Local Electronic Structure in Wild-Type and Arctic Amyloid-Β42}},
author = {kushal patil},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010287/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010287/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Conformational Heterogeneity and Local Electronic Structure in Wild-Type and Arctic Amyloid-Β42
AU - kushal patil
PY - 2026
DA - 2026/10/12
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010287/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010287/v1
AB - 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.
ER -