Mechanical and thermodynamic properties of Aβ₄₂, Aβ₄₀ and α-synuclein fibrils: A coarse-grained method to complement experimental studies

Abstract

Mechanical and thermodynamic properties of Aβ 42 , Aβ 40 , and α-1 synuclein fibrils: A coarse-grained method to complement experimen-2 tal studies 3 Abstract 12 We perform molecular dynamics simulation on several relevant biological fibrils associated with 13 neurodegenerative diseases such as Aβ 40 , Aβ 42 , and α-synuclein systems to obtain a molecular un-14 derstanding and interpretation of nanomechanical characterization experiments. The computational 15 method is versatile and addresses a new subarea within the mechanical characterization of hetero-16 geneous soft materials. We investigate both the elastic and thermodynamic properties of the biolog-17 ical fibrils in order to substantiate experimental nanomechanical characterization techniques that 18 are quickly developing and reaching dynamic imaging with video rate capabilities. The computa-19 tional method qualitatively reproduces results of experiments with biological fibrils, validating its 20 use in extrapolation to macroscopic material properties. Our computational techniques can be used 21 for the co-design of new experiments aiming to unveil nanomechanical properties of biological fib-22 rils from a molecular understanding point of view. Our approach allows a comparison of diverse 23 elastic properties based on different deformation , i.e. tensile (Y L ), shear (S), and indentation (Y T ). 24From our analysis, we find a significant elastic anisotropy between axial and transverse directions 25 (i.e. Y T > Y L ) for all systems. Interestingly, our results indicate a higher mechanostability in the 26 case of Aβ 42 fibrils than in the case of Aβ 40 , suggesting a significant correlation between mechan-27 ical stability and aggregation propensity (rate) in amyloid systems, that is, the higher the mechan-28 ical stability the faster the fibril formation. Finally, we find that α-synuclein fibrils are thermally 29 less stable than β -amyloid fibrils. We anticipate that our molecular-level analysis of the mechan-30 1 ical response under different deformation conditions for the range of fibrils considered here will 31 provide significant insights for the experimental observations. 32Background: Nanomechanical characterization of a single biological fibril is generally a challenge 33 due to the typical thermal motion. Here, we propose a computational protocol that can assist ex-34 periment in elucidating the molecular background of the mechanical response in fibrils related to 35 neurodegenerative diseases. 36 Results: We performed a systematic comparison of mechanical properties of different biological 37 fibrils involved in neurodegenerative diseases. Our results show a higher mechanocanostability in 38 case of Aβ 42 fibrils than in the case of Aβ 40 . This effect is observed for all different types of me-39 chanical deformation. Moreover, the α-synuclein fibril shows a large anisotropy (i.e. Y T > Y L ) in 40 comparison with β -amyloid fibrils, and it is thermally less stable than β -amyloid fibrils. 41 Keywords 42 Atomic Force Microscopy, β -amyloid; ...

May the force be with you: the role of hyper-mechanostability of the bone sialoprotein binding protein during early stages of Staphylococci infections

“…CG-SMD simulations have proven to bridge the force-loading gap between in vitro SMFS data with in silico data obtained from aa-SMD simulations, distanced by orders of magnitude. 54 In addition, CG-SMD simulations require much less computational power, 59,60 enabling us to explore pulling speeds unfeasible to simulate via aa-SMD. 54 Here, we showed that Bbp:Fgα complex can withstand forces even higher than the previously investigated SdrG:Fgβ complex.…”