title: Role of sequence and structural polymorphism on the mechanical properties of amyloid fibrils.
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.
authors.affiliation: Department of Mechanical Engineering, Korea University, Seoul, Republic of Korea ; Department of Mechanical Engineering, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Gwonchan
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Department of Mechanical Engineering, Korea University, Seoul, Republic of Korea.
authors.forename: Myeongsang
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Mechanical Engineering, Korea University, Seoul, Republic of Korea.
authors.forename: Jae In
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Mechanical Engineering, Korea University, Seoul, Republic of Korea.
authors.forename: Sungsoo
authors.initials: S
authors.lastname: Na
authors.affiliation: Biomechanics Laboratory, College of Sport Science, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Kilho
authors.initials: K
authors.lastname: Eom
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics; D055595:Mechanical Phenomena; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics; D017433:Protein Structure, Secondary; D020539:Sequence Analysis, Protein; D013816:Thermodynamics; D014732:Vibration
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D050505:Mutant Proteins