Simulated mechanical testing of amyloid fibril structures using molecular dynamics simulations with enhanced sampling

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Biophysical Journal




3 Supplement 1



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Amyloid fibrils are a class of locally ordered protein aggregates known for their well-documented association with protein misfolding diseases such as Alzheimer's disease. These fibrils are characterized by the highly conserved cross- secondary structure spanning the fibril growth axis. X-ray crystallography is a leading experimental technique for resolving amyloid fibril structures from crystallized proteins. These experimental techniques have made invaluable contributions to our understanding of many protein structures; however, inherent limitations such as crystallization conditions that are far removed from physiological conditions, leave open the possibility that crystal structures generated under such circumstances may not be representative of amyloid fibril structures formed under in vivo conditions. Another experimental technique used to study fibril structures is atomic force microscopy (AFM). AFM has been used to determine key structural forces relating to the fibril steric zipper, as well as mechanical properties of amyloid fibrils, such as Young's modulus (a stiffness measure). Here, we demonstrate an approach that uses molecular dynamics (MD) simulations to study select mechanical properties of an amyloid fibril constructed from a crystal unit cell of human insulin chain B included in the Protein Data Bank as an amyloid fibril structure (PDB ID: 3hyd). Specifically, Steered MD was used to apply artificial forces to the fibrils to the point of breakage, while maintaining experimentally similar conditions to the AFM experiments. Mechanical characteristics such as stress-strain curves, were compared to measurements from AFM experiments. The MD simulations matched well with the experimental measurements from the AFM, suggesting that our in silico mechanical testing methodology can be used to provide supporting data for amyloid fibril structures resolved using x-ray crystallography.