The Effect of Structural Heterogeneity on the Conformation and Stability of Aβ-Tau Mixtures

H. Choi, M. Lee, H.S. Park and S-S Na
RSC Advances 2016; 6:52236-52247

Abstract

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.

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Force-Dependent Mechanical Unfolding Pathways of GFP

P. Cao, W. Tao and H.S. Park
Extreme Mechanics Letters 2016; 8:251-256
(Special Issue on Nanomechanics: Bridging Spatial and Temporal Scales)

Abstract

We characterize the force-dependent unfolding pathways and intermediate configurations of the green fluorescence protein (GFP) using novel atomistic simulations based on potential energy surface exploration. By using this approach, we are able to unfold GFP to significantly longer end-to-end distances, i.e. 40 nm, as compared to that seen in previous atomistic simulation studies. We find that there are four intermediate states between 5 and 40 nm end-to-end distance, where the intermediate configurations and unfolding pathways are strongly force-dependent. We additionally calculate the force-dependent lifetime of the 14 nm αβ1 intermediate, and demonstrate that it obeys Bell's formula.

This paper is available in PDF form .

β-Sheet-Like Formation During the Mechanical Unfolding of Prion Protein

W. Tao, G. Yoon, P. Cao, K. Eom and H.S. Park
Journal of Chemical Physics 2015; 143:125101

Abstract

Single molecule experiments and simulations have been widely used to characterize the unfolding and folding pathways of different proteins. However, with few exceptions, these tools have not been applied to study prion protein, PrPC, whose misfolded form PrPSc can induce a group of fatal neurodegenerative diseases. Here, we apply novel atomistic modeling based on potential energy surface exploration to study the constant force unfolding of human PrP at time scales inaccessible with standard molecular dynamics. We demonstrate for forces around 100 pN, prion forms a stable, three-stranded β-sheet-like intermediate configuration containing residues 155-214 with a lifetime exceeding hundreds of nanoseconds. A mutant without the disulfide bridge shows lower stability during the unfolding process but still forms the three-stranded structure. The simulations thus not only show the atomistic details of the mechanically-induced structural conversion from the native α-helical structure to the β-rich-like form, but also lend support to the structural theory that there is a core of the recombinant PrP amyloid, a misfolded form reported to induce transmissible disease, mapping to C-terminal residues 160-220.

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The Molecular Mechanism of Conformational Changes of the Triplet Prion Fibrils for pH

H. Choi, H.J. Chang, Y. Shin, H.S. Park, G. Yoon and S. Na
RSC Advances 2015; 5:49263-49269

Abstract

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 experimentalal results. Finally, we calculated the mechanical properties of the triplet prion fibrils to elucidate its variations in the infectious state.

This paper is available in PDF form .

Cofilin Reduces The Mechanical Properties of Actin Filaments: Approach with Coarse-Grained Methods

J.I. Kim, J. Kwon, I. Baek, H.S. Park and S. Na
Physical Chemistry Chemical Physics 2015; 17:8148-8158

Abstract

An actin filament is an essential cytoskeleton protein in a cell. Various proteins bind to actin for cell functions such as migration, division, and shape control. ADF/cofilin is a protein that severs actin filaments and is related to their dynamics. Actin is known to have excellent mechanical properties. Binding cofilin reduces its mechanical properties, and is related to the severing process. In this research, we applied a coarse-grained molecular dynamics simulation (CGMD) to obtain actin filaments and cofilin-bound actin (cofilactin) filaments. Using these two obtained models, we constructed an elastic network model-based structure and conducted a normal mode analysis. Based on the low-frequency normal modes of the filament structure, we applied the continuum beam theory to calculate the mechanical properties of the actin and cofilactin filaments. The CGMD provided structurally accurate actin and cofilactin filaments in relation to the mechanical properties, which showed good agreement with the established experimental results.

This paper is available in PDF form .

The Role of Binding Site on the Mechanical Unfolding Mechanism of Ubiquitin

P. Cao, G. Yoon, W. Tao, K. Eom and H.S. Park
Scientific Reports 2015; 5:8757

Abstract

We apply novel atomistic simulations based on potential energy surface exploration to investigate the constant force-induced unfolding of ubiquitin. At the experimentally-studied force clamping level of 100 pN, we find a new unfolding mechanism starting with the detachment between β5 and β3 involving the binding site of ubiquitin, the Ile44 residue. This new unfolding pathway leads to the discovery of new intermediate configurations, which correspond to the end-to-end extensions previously seen experimentally. More importantly, it demonstrates the novel finding that the binding site of ubiquitin can be responsible not only for its biological functions, but also its unfolding dynamics. We also report in contrast to previous single molecule constant force experiments that when the clamping force becomes smaller than about 300 pN, the number of intermediate configurations increases dramatically, where almost all unfolding events at 100 pN involve an intermediate configuration. By directly calculating the life times of the intermediate configurations from the height of the barriers that were crossed on the potential energy surface, we demonstrate that these intermediate states were likely not observed experimentally due to their lifetimes typically being about two orders of magnitude smaller than the experimental temporal resolution.

This paper is available in PDF form .