Myeongsang Lee

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

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.

Relationship between structural composition and material properties of polymorphic hIAPP fibrils

Amyloid proteins are misfolded, denatured proteins that are responsible for causing several degenerative and neuro-degenerative diseases. Determining the mechanical stability of these amyloids is crucial for understanding the disease mechanisms, which will guide us in treatment. Furthermore, many research groups recognized amyloid proteins as functional biological materials that can be used in nanosensors, bacterial biofilms, coatings, etc. Many in vitro studies have been carried out to determine the characteristics of amyloid proteins via force spectroscopy methods, atomic force microscopy, and optical tweezers. However, computational methods (e.g. molecular dynamics and elastic network model) not only reveal the mechanical properties of the amyloid proteins, but also provide more in-depth information about the amyloids by presenting a visualization of their conformational changes. In this study, we evaluated the various material properties and behaviors of four different polymorphic structures of human islet amyloid polypeptide (hIAPP) by using steered molecular dynamics (SMD) simulations under tensile conditions. From our results, we examined how these mechanical properties may differ with respect to the structural formation of amyloid proteins.

Influence of Aromatic Residues on the Material Characteristics of Aβ Amyloid Protofibrils at the Atomic Scale

Amyloid fibrils, which cause a number of degenerative diseases, are insoluble under physiological conditions and are supported by native contacts. Recently, the effects of the aromatic residues on the Aβ amyloid protofibril were investigated in a ThT fluorescence study. However, the relationship between the material characteristics of the Aβ protofibril and its aromatic residues has not yet been investigated on the atomic scale. Here, we successfully constructed wild-type (WT) and mutated types of Aβ protofibrils by using molecular dynamics simulations. Through principle component analysis, we established the structural stability and vibrational characteristics of F20L Aβ protofibrils and compared them with WT and other mutated models such as F19L and F19LF20L. In addition, structural stability was assessed by calculating the elastic modulus, which showed that the F20L model has higher values than the other models studied. From our results, it is shown that aromatic residues influence the structural and material characteristics of Aβ protofibrils.

End Capping Alters the Structural Characteristics and Mechanical Properties of Transthyretin (105-115) Amyloid Protofibrils

Pathological amyloid proteins are associated with degenerative and neurodegenerative diseases. These amyloid proteins develop as oligomer, fibrillar, and plaque forms, due to the denatured and unstable status of the amyloid monomers. Specifically, the development of fibrillar amyloid proteins has been investigated through several experimental studies. To understand the generation of amyloid fibrils, environmental factors such as point mutations, pH, and polymorphic characteristics have been considered. Recently, amyloid fibril studies related to end-capping effects have been conducted to understand amyloid fibril development. However, atomic-level studies to determine the stability and mechanical properties of amyloid fibrils based on end capping have not been undertaken. In this study, we show that end capping alters the structural characteristics and conformations of transthyretin (TTR) amyloid fibrils by using molecular dynamics (MD) simulations. Variation in the structural conformations and characteristics of the TTR fibrils through end capping are observed, due to the resulting electrostatic energies and hydrophobicity characteristics. Moreover, the end capping changes the mechanical properties of TTR fibrils. Our results shed light on amyloid fibril formation under end-capping conditions.

Effects of lysine residues on structural characteristics and stability of tau proteins

Pathological amyloid proteins have been implicated in neuro-degenerative diseases, specifically Alzheimers, Parkinsons, Lewy-body diseases and prion related diseases. In prion related diseases, functional tau proteins can be transformed into pathological agents by environmental factors, including oxidative stress, inflammation, Aβ-mediated toxicity and covalent modification. These pathological agents are stable under physiological conditions and are not easily degraded. This un-degradable characteristic of tau proteins enables their utilization as functional materials to capturing the carbon dioxides. For the proper utilization of amyloid proteins as functional materials efficiently, a basic study regarding their structural characteristic is necessary. Here, we investigated the basic tau protein structure of wild-type (WT) and tau proteins with lysine residues mutation at glutamic residue (Q2K) on tau protein at atomistic scale. We also reported the size effect of both the WT and Q2K structures, which allowed us to identify the stability of those amyloid structures.

Morphology and mechanical properties of multi-stranded amyloid fibrils probed by atomistic and coarse-grained simulations

Amyloid fibrils are responsible for pathogenesis of various diseases and exhibit the structural feature of an ordered, hierarchical structure such as multi-stranded helical structure. As the multi-strandedness of amyloid fibrils has recently been found to be highly correlated with their toxicity and infectivity, it is necessary to study how the hierarchical (i.e. multi-stranded) structure of amyloid fibril is formed. Moreover, although it has recently been reported that the nanomechanics of amyloid proteins plays a key role on the amyloid-induced pathogenesis, a critical role that the multi-stranded helical structure of the fibrils plays in their nanomechanical properties has not fully characterized. In this work, we characterize the morphology and mechanical properties of multi-stranded amyloid fibrils by using equilibrium molecular dynamics simulation and elastic network model. It is shown that the helical pitch of multi-stranded amyloid fibril is linearly proportional to the number of filaments comprising the amyloid fibril, and that multi-strandedness gives rise to improving the bending rigidity of the fibril. Moreover, we have also studied the morphology and mechanical properties of a single protofilament (filament) in order to understand the effect of cross-β structure and mutation on the structures and mechanical properties of amyloid fibrils. Our study sheds light on the underlying design principles showing how the multi-stranded amyloid fibril is formed and how the structure of amyloid fibrils governs their nanomechanical properties.

Conformational changes of Aβ (1–42) monomers in different solvents

Amyloid proteins are known to be the main cause of numerous degenerative and neurodegenerative diseases. In general, amyloids are misfolded from monomers and they tend to have β-strand formations. These misfolded monomers are then transformed into oligomers, fibrils, and plaques. It is important to understand the forming mechanism of amyloids in order to prevent degenerative diseases to occur. Aβ protein is a highly noticeable protein which causes Alzheimers disease. It is reported that solvents affect the forming mechanism of Aβ amyloids. In this research, Aβ1-42 was analyzed using an all-atom MD simulation with the consideration of effects induced by two disparate solvents: water and DMSO. As a result, two different conformation changes of Aβ1-42 were exhibited in each solvent. It was found that salt-bridge of Asp23 and Lys28 in Aβ1-42 was the key for amyloid folding based on the various analysis including hydrogen bond, electrostatic interaction energy and salt-bridge distance. Since this salt-bridge region plays a crucial role in initiating the misfolding of Aβ1-42, this research may shed a light for studies related in amyloid folding and misfolding.

The effect of structural heterogeneity on the conformation and stability of Aβ–tau mixtures

Oligomeric and fibrillar amyloids, which cause neurodegenerative diseases, are typically formed through repetitive fracture and elongation processes involving single homogeneous amyloid monomers. However, experimental and computational methods have shown that the amyloid proteins could be composed of heterogeneous amyloid segments. Specifically, owing to the polymorphism of amyloids under physiological conditions, it is crucial to understand the structural characteristics of heterogeneous amyloids in detail by considering their specific mutations and polymorphic nature. Therefore, in this study we used atomistic simulations to reveal the various structural characteristics of heterogeneous amyloids, which are amyloids composed of amyloid beta (Aβ) and mutated tau proteins. Furthermore, we showed that the different characteristics and conformations of Aβ–tau mixtures are the cause of the different types of tau proteins based on Aβ segments. Interestingly, we found that valine and lysine residues have a significant impact on the structural conformation and stability of the heterogeneous Aβ–tau mixtures. We also showed that two types of binding are key to understanding the different binding features and mechanical reactions to tensile load. This study sheds light on the assembly features of heterogeneous Aβ–tau mixtures as neurodegenerative disease factors.

Sodium chloride's effect on self-assembly of diphenylalanine bilayer

Understanding self‐assembling peptides becomes essential in nanotechnology, thereby providing a bottom‐up method for fabrication of nanostructures. Diphenylalanine constitutes an outstanding building block that can be assembled into various nanostructures, including two‐dimensional bilayers or nanotubes, exhibiting superb mechanical properties. It is known that the effect of the ions is critical in conformational and chemical interactions of bilayers or membranes. In this study, we analyzed the effect of sodium chloride on diphenylalanine bilayer using coarse‐grained molecular dynamics simulations, and calculated the bending Youngs modulus and the torsional modulus by applying normal modal analysis using an elastic network model. The results showed that sodium chloride dramatically increases the assembling efficiency and stability, thereby promising to allow the precise design and control of the fabrication process and properties of bio‐inspired materials.

Effects of End-Terminal Capping on Transthyretin (105–115) Amyloid Protofibrils Using Steered Molecular Dynamics

Numerous degenerative diseases are associated with amyloidosis, which can be caused by amyloid proteins. These amyloid proteins are generated from misfolded and denatured amyloid monomers under physiological conditions. Changes in protonation state, pH, ionic strength, and temperature, in addition to mutations, are related to the promotion of amyloidosis. Specifically, an understanding of the mechanical characteristics of amyloid protofibrils is important, since amyloid growth proceeds by a mechanism involving cycles of fragmentation and elongation. However, there remains a lack of knowledge of amyloid structural conformations and their mechanical characteristics, particularly considering end-terminal capping effects. In the present study, we investigated the mechanical characteristics of transthyretin amyloid protein (TTR), which have been implicated in cardiovascular disease, and specifically considered the contribution of end-terminal capping effects. Using steered molecular dynamics (SMD) simulations, we report different structural behaviors between uncapped and capped TTR amyloid protofibrils. We show that end-terminal capping strengthens the structural stability and improves the mechanical properties of amyloid protofibrils. This study provides useful information concerning the structural and mechanical characteristics of TTR amyloid protofibrils, with a particular emphasis on end-terminal capping effects.