Bioelectrochemistry (Amsterdam, Netherlands) · 2026
Irreversible mechanical weakening of amyloid-β K16 mutants via electrostatic torque.
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Shin Hongchul, Lim Songhee, Yeom Junbin, Jeong Hae-Chang, Yoon Taeyoung
Аннотация
BACKGROUND: Amyloid-beta (Aβ) fibrils act as the structural core of Alzheimer's disease pathology and maintain exceptional mechanical stability through dense β-sheet networks. However, the molecular mechanisms through which external physical stimuli disrupt these robust scaffolds remain poorly understood, particularly the residue-specific responses.
METHODS: Here, we systematically evaluated the structural collapse and mechanical attenuation of Aβ fibrils and their K16 mutants, including the charge-reversal K16D and bulky K16W, under a 1.0 V/nm electric field (EF) using molecular dynamics (MD) simulations.
RESULTS: We demonstrated that this external stimulus persistently disrupts the β-sheet hydrogen-bond network within the simulated recovery window and leads to a drastic reduction in Young's modulus driven by dipole-field misalignment. Notably, this response was highly mutation dependent since the K16D mutant exhibited severe orientation-dependent collapse due to an amplified electrostatic torque, whereas K16W maintained its structural resistance via enhanced steric packing. Furthermore, EF induced a sustained increase in the solvent-accessible surface area (SASA).
CONCLUSION: These findings suggest that external EF can serve as a potent physical modulator to destabilize pathogenic amyloid aggregates, potentially overcoming the physical barrier of dense plaques, enhancing the penetration and efficacy of therapeutic agents.
METHODS: Here, we systematically evaluated the structural collapse and mechanical attenuation of Aβ fibrils and their K16 mutants, including the charge-reversal K16D and bulky K16W, under a 1.0 V/nm electric field (EF) using molecular dynamics (MD) simulations.
RESULTS: We demonstrated that this external stimulus persistently disrupts the β-sheet hydrogen-bond network within the simulated recovery window and leads to a drastic reduction in Young's modulus driven by dipole-field misalignment. Notably, this response was highly mutation dependent since the K16D mutant exhibited severe orientation-dependent collapse due to an amplified electrostatic torque, whereas K16W maintained its structural resistance via enhanced steric packing. Furthermore, EF induced a sustained increase in the solvent-accessible surface area (SASA).
CONCLUSION: These findings suggest that external EF can serve as a potent physical modulator to destabilize pathogenic amyloid aggregates, potentially overcoming the physical barrier of dense plaques, enhancing the penetration and efficacy of therapeutic agents.