Research Article: Role of Sequence and Structural Polymorphism on the Mechanical Properties of Amyloid Fibrils

Date Published: February 14, 2014

Publisher: Public Library of Science

Author(s): Gwonchan Yoon, Myeongsang Lee, Jae In Kim, Sungsoo Na, Kilho Eom, Jie Zheng.


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.

Partial Text

For last decades, it has been observed that denatured proteins are prone to form a self-assembled structure [1], particularly fibril structure referred to as “amyloid fibril” [2]–[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]. For instance, 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]. This amyloid fibril in human pancreas is able to replace the β cell performing the insulin secretion in pancreas, which results in amyloid fibril-driven inhibition of insulin secretion leading to diabetes. In particular, amyloid fibril is able to disrupt the cell membrane leading to cellular apoptosis, which is attributed to the bending rigidity of amyloid fibril being higher than that of cell membrane [9].

In this work, we have studied the mechanical properties of amyloid fibrils using all-atom explicit water MD simulation along with continuum mechanics theory. Our study shows that the mechanical properties of amyloid fibrils are closely related to their molecular architectures, particularly the steric zipper patterns, and that the structure-dependent mechanical properties of amyloid fibrils are critically affected by genetic mutation. Specifically, amino acid sequence determines chemical interaction between β sheet layers constituting an amyloid fibril, and consequently, its mechanical properties. Our study sheds light on sequence-structure-property relationship of amyloid fibril, which highlights the design principles that provide an insight into how to tune the mechanical properties of an amyloid fibril based on its molecular structure and sequence.