Amyloid fibrils, protein aggregates linked to Alzheimer’s and related neurological diseases, maintain a conserved cross-β structure in which hydrogen bonding drives protofilament assembly. While experimental techniques such as atomic force microscopy (AFM) can measure fibril stiffness and even produce stress-strain curves, they lack atomistic structural detail. At the same time, X-ray crystal structures offer atomistic structural detail but do not offer opportunities to probe fibril mechanical properties. To address this, we employed large-scale explicit solvent molecular dynamics (MD) simulations to model the mechanical breakage of a human insulin chain B fibril (PDB ID: 3HYD). Using steered molecular dynamics (SMD), we simulated AFM pulling forces, generating force-displacement profiles for direct comparison to experimental data. Building on prior vacuum and implicit solvent studies, our configuration incorporates explicit water molecules and a 75 nm, 640-layer fibril totaling ∼7 million atoms. By scaling both fibril length and simulation environment, we aim to more closely approximate experimental breakage conditions with greater fidelity and better replicate AFM measurements. Preliminary results from the first explicit solvent trajectory yield a smooth force-displacement profile with a peak of ∼1200 pN, within the range of AFM experiments and distinct from the higher force, and noisier profiles observed in vacuum simulations. These findings suggest that solvent and system size directly influence fibril stiffness and fracture metrics. Ongoing efforts focus on performing additional repetitions to establish reproducibility, compare the results with published stress-strain curves measured using AFM experiments, and provide deeper insight into the molecular mechanics underlying amyloid fibril stability.
Gadingan et al. (Sun,) studied this question.