Inchul Baek

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.

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.

Understanding structural characteristics of out-of-register hIAPP amyloid proteins via molecular dynamics

Amyloid oligomers are implicated in several neurodegenerative diseases; studies have shown oligomeric amyloids form fibrillary amyloids and have toxic effects on cell function. Several experimental and computational studies have investigated in-register amyloids and their characteristics. However, recently, out-of-register amyloid structures have been observed and their inherent weak structural stability exhibits higher toxicity under physiological conditions compared to that of in-register amyloids. Specifically, by varying the size of oligomeric hIAPP out-of-register structures from 4 layers to 20 layers, we successfully analyzed the structural characteristics of fibrillary out-of-register hIAPP; the critical structure size of out-of-register hIAPP is related to fibrillar growth from protofibrils. Through the structural analysis of out-of-register hIAPP, we shed light on the fibrillar growth mechanism of out-of-register hIAPP oligomer in detail.

Biophysical characterization of cofilin-induced extension–torsion coupling in actin filaments

Cofilin makes the actin filament flexible and thermally unstable by disassembling the filament and inducing bending and torsional compliance. Actin monomers bound to cofilin are able to chemically and mechanically interact in response to external forces. In this study, we performed two molecular dynamics tensile tests for actin and cofilactin filaments under identical conditions. Surprisingly, cofilactin filaments were found to be twisted, generating shear stress caused by torsion. Additionally, analysis by plane stress assumption indicated that the extension-torsion coupling effect increases the amount of principal stress by 10%. Using elasticity and solid mechanics theories, our study elucidates the role of cofilin in the disassembly of actin filaments under tensile forces.

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.

Structural analysis of oligomeric and protofibrillar Aβ amyloid pair structures considering F20L mutation effects using molecular dynamics simulations.

Aβ amyloid proteins are involved in neuro‐degenerative diseases such as Alzheimers, Parkinsons, and so forth. Because of its structurally stable feature under physiological conditions, Aβ amyloid protein disrupts the normal cell function. Because of these concerns, understanding the structural feature of Aβ amyloid protein in detail is crucial. There have been some efforts on lowering the structural stabilities of Aβ amyloid fibrils by decreasing the aromatic residues characteristic and hydrophobic effect. Yet, there is a lack of understanding of Aβ amyloid pair structures considering those effects. In this study, we provide the structural characteristics of wildtype (WT) and phenylalanine residue mutation to leucine (F20L) Aβ amyloid pair structures using molecular dynamics simulation in detail. We also considered the polymorphic feature of F20L and WT Aβ pair amyloids based on the facing β‐strand directions between the amyloid pairs. As a result, we were able to observe the varying effects of mutation, polymorphism, and protofibril lengths on the structural stability of pair amyloids. Furthermore, we have also found that opposite structural stability exists on a certain polymorphic Aβ pair amyloids depending on its oligomeric or protofibrillar state, which can be helpful for understanding the amyloid growth mechanism via repetitive fragmentation and elongation mechanism. Proteins 2017; 85:580–592.

Mechanically inferior constituents in spider silk result in mechanically superior fibres by adaptation to harsh hydration conditions: a molecular dynamics study

Spider silk exhibits mechanical properties such as high strength and toughness that are superior to those of any man-made fibre (Bourzac 2015 Nature 519, S4–S6 (doi:10.1038/519S4a)). This high strength and toughness originates from a combination of the crystalline (exhibiting robust strength) and amorphous (exhibiting superb extensibility) regions present in the silk (Asakura et al. 2015 Macromolecules 48, 2345–2357 (doi:10.1021/acs.macromol.5b00160)). The crystalline regions comprise a mixture of poly-alanine and poly-glycine-alanine. Poly-alanine is expected to be stronger than poly-glycine-alanine, because alanine exhibits greater interactions between the strands than glycine (Tokareva et al. 2014 Acta Biomater. 10, 1612–1626 (doi:10.1016/j.actbio.2013.08.020)). We connect this characteristic sequence to the interactions observed upon the hydration of spider silk. Like most proteinaceous materials, spider silks become highly brittle upon dehydration, and thus water collection is crucial to maintaining its toughness (Gosline et al. 1986 Endeavour 10, 37–43 (doi:10.1016/0160-9327(86)90049-9)). We report on the molecular dynamic simulations of spider silk structures with different sequences for the crystalline region of the silk structures, of wild-type (WT), poly-alanine, and poly-glycine-alanine. We reveal that the characteristic sequence of spider silk results in the β-sheets being maintained as the degree of hydration changes and that the high water collection capabilities of WT spider silk sequence prevent the silk from becoming brittle and weak in dry conditions. The characteristic crystalline sequence of spider dragline silk is therefore relevant not for maximizing the interactions between the strands but for adaption to changing hydration conditions to maintain an optimal performance even in harsh conditions.

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.

Structural analysis of F20L oligomeric and protofibrillar amyloid pair structures using molecular dynamics simulations

Ap amyloid protein is representative agent, which is involved in neuro-degenerative diseases. Due to the undegrading characteristics under physiological conditions, understanding the structural characteristics of Aβ amyloid protein in detail is crucial. Many efforts have made on the lowering the structural stabilities of Aβ amyloid protein by decreasing the aromatic residues characteristic and hydrophobic effect. However, there lacks an understanding of Aβ amyloid pair structures in detail. In this work, we provide the structural characteristics of Aβ amyloid pair structures by selective leucine residue mutation on phenylalanine residue (F20L). We also considered the polymorphic feature of F20L Aβ amyloid pair based on NN, CC and NC compositions. Furthermore, we found the structural difference of oligomeric and fibrillar NC F20L Aβ amyloid pair structures in detail.