Abstract
Amyloid fibrils playing a critical role in disease expression, have recently been found to exhibit the excellent mechanical properties such as elastic modulus in the order of 10 GPa, which is comparable to that of other mechanical proteins such as microtubule, actin filament, and spider silk. These remarkable mechanical properties of amyloid fibrils are correlated with their functional role in disease expression. This suggests the importance in understanding how these excellent mechanical properties are originated through self-assembly process that may depend on the amino acid sequence. However, the sequence-structure-property relationship of amyloid fibrils has not been fully understood yet. In this work, we characterize the mechanical properties of human islet amyloid polypeptide (hIAPP) fibrils with respect to their molecular structures as well as their amino acid sequence by using all-atom explicit water molecular dynamics (MD) simulation. The simulation result suggests that the remarkable bending rigidity of amyloid fibrils can be achieved through a specific self-aggregation pattern such as antiparallel stacking of β strands (peptide chain). Moreover, we have shown that a single point mutation of hIAPP chain constituting a hIAPP fibril significantly affects the thermodynamic stability of hIAPP fibril formed by parallel stacking of peptide chain, and that a single point mutation results in a significant change in the bending rigidity of hIAPP fibrils formed by antiparallel stacking of β strands. This clearly elucidates the role of amino acid sequence on not only the equilibrium conformations of amyloid fibrils but also their mechanical properties. Our study sheds light on sequence-structure-property relationships of amyloid fibrils, which suggests that the mechanical properties of amyloid fibrils are encoded in their sequence-dependent molecular architecture.
Highlights
For last decades, it has been observed that denatured proteins are prone to form a self-assembled structure [1], fibril structure referred to as ‘‘amyloid fibril’’ [2,3,4], which is ubiquitously found in patients suffering from various diseases ranging from neurodegenerative disease [5] to cardiovascular disease [6] and type II diabetes [7,8]
In order to quantitatively characterize the stability of such polymorphic structures, we take into account the RMSDs of polymorphic human islet amyloid polypeptide (hIAPP) fibrils
We have studied the mechanical properties of amyloid fibrils using all-atom explicit water molecular dynamics (MD) simulation along with continuum mechanics theory
Summary
It has been observed that denatured proteins are prone to form a self-assembled structure [1], fibril structure referred to as ‘‘amyloid fibril’’ [2,3,4], which is ubiquitously found in patients suffering from various diseases ranging from neurodegenerative disease [5] to cardiovascular disease [6] and type II diabetes [7,8]. Islet amyloid polypeptide (IAPP) chains are aggregated to form an one-dimensional fibril structure, and such IAPP fibril has been found in patients suffering from type II diabetes [7]. The size-dependent elastic modulus of disease-specific prion fibril provides an insight into the length scale of prion fibril that can act as a seed leading to prion infectivity [13]. These observations clearly demonstrate that the functional role of amyloid fibril on the disease expression may be highly correlated with the mechanical properties of amyloid fibrils
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
