Hyunsung Choi

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.

The molecular mechanism of conformational changes of the triplet prion fibrils for pH

The HET-s prion fibril, which is found in the filamentous fungus Podospora anserina, exhibits conformational changes due to variations in pH. Here, we explain the effects of changing pH on the conformational changes of fibrils through the fundamental eigenmodes of the fibrils, in particular the torsional and bending modes, using a parameter free elastic network model. In particular, the motion resulting from these fundamental eigenmodes is found to be very similar to the conformational changes stimulated by pH variations as shown in previous experimental results. Finally, we calculated the mechanical properties of the triplet prion fibrils to elucidate its variations in the infectious state.

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.

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.

Mechanical features of various silkworm crystalline considering hydration effect via molecular dynamics simulations

Silk materials are receiving significant attention as base materials for various functional nanomaterials and nanodevices, due to its exceptionally high mechanical properties, biocompatibility, and degradable characteristics. Although crystalline silk regions are composed of various repetitive motifs with differing amino acid sequences, how the effect of humidity works differently on each of the motifs and their structural characteristics remains unclear. We report molecular dynamics (MD) simulations on various silkworm fibroins composed of major motifs (i.e. (GAGAGS)n, (GAGAGA)n, and (GAGAGY)n) at varying degrees of hydration, and reveal how each major motifs of silk fibroins change at each degrees of hydration using MD simulations and their structural properties in mechanical perspective via steered molecular dynamics simulations. Our results explain what effects humidity can have on nanoscale materials and devices consisting of crystalline silk materials.

Capping effects on polymorphic Aβ16–21 amyloids depend on their size: A molecular dynamics simulation study

Understanding Aβ amyloid oligomers associated with neuro-degenerative diseases is needed due to their toxic characteristics and mediation of amyloid fibril growth. Depending on various physiological circumstances such as ionic strength, metal ion, and point-residue mutation, oligomeric amyloids exhibit polymorphic behavior and structural stabilities, i.e. showing different conformation and stabilities. Specifically, experimental and computational researchers have found that the capping modulates the physical and chemical properties of amyloids by preserving electrostatic energy interactions, which is one of the dominant factors for amyloid stability. Still, there is no detailed knowledge for the polymorphic amyloids with reflecting the terminal capping effects. In the present study, we investigated the role of terminal capping (i.e. N-terminal acetylation and C-terminal amidation) on polymorphic Aβ16-21 amyloid oligomer and protofibrils via molecular dynamics (MD) simulations. We found that the capping effects have differently altered the conformation of polymorphic antiparallel-homo and -hetero Aβ16-21 amyloid oligomer, but not Aβ16-21 amyloid protofibrils. However, regardless of polymorphic composition of the amyloids, the capping induces the thermodynamic instabilities of Aβ16-21 amyloid oligomers, but does not show any distinct affect on Aβ16-21 amyloid protofibrils. Specifically, among the molecular mechanic factors, electrostatic energy dominantly contributes the thermodynamic stability of the Aβ16-21 amyloids. We hope that our computation study about the role of the capping effects on the polymorphic amyloids will facilitate additional efforts to enhance degradation of amyloids and to design a selective drug in the future.

Structure-Property Relationship of Amyloidogenic Prion Nanofibrils

The structure and its property for the prion nanofibrils, which exhibit self-assembled steric zipper, amyloid fibrils, are described in this chapter. There is the belief of origin for the infectiousness of the prion can be its molecular structure. It is due to the amyloid toxicity, which is related to its beta sheet rich molecular structure and self-aggregated long fibrils. There is evidence that the difference between PrPc and PrPsc is transitioned beta sheet from alpha helix to self-assemble and then to the amyloidogenic fibrils. Therefore, the scope of this chapter is the amyloidogenic structural characteristics of prion fibrils and its relationship to the property. The molecular structural characteristics can be changed by properties such as affinity, toxicity, infectivity, and so on, so this is a key factor to understand the origin of prion disease and develop the therapeutic strategy. One of the main properties of amyloid fibrils that we want to describe here is mechanical property such as dynamic property and material property for prion nanofibrils. This chapter can shed light on understanding the infectious characteristics of prion and the relationship of its molecular structures.

Impact of solvent on silk materials

Natural silk is one of the toughest materials known, and combined with its unique properties such as biocompatibility, dyeability, silk is sought in many fields such as biomedical, textile industry, engineering and et cetera. Many groups have tried to mass produce synthetic silk matching the properties of natural silk, but have yet to succeed. This study focuses on investigating the effect of solvent on the properties of silk material, to better understand the ideal conditions for producing synthetic silk that matches natural silk, via molecular dynamics simulations, and through the use of methods such as Euler-Bernoulli beam theory, principal component analysis, hydrogen bond and RMSD analysis. We report the effect of solvent on each components of silk that can be applied to various types of silk.