Revisiting the Ramachandran plot based on statistical analysis of static and dynamic characteristics of protein structures.

Ramachandran plots, which describe protein structures by plotting the dihedral angle pairs of the backbone on a two-dimensional plane, have played an important role in structural biology over the past few decades. However, despite continued discovery of new protein structures to date, the Ramachandran plot is still constructed by only a small number of data points, and further it cannot reflect the steric information of proteins. Here, we investigated the secondary structure of proteins in terms of static and dynamic characteristics. As for static feature, the Ramachandran plot was revisited for the dataset consisting of 9,148 non-redundant high-resolution protein structures released in the protein data bank until April 1, 2022. By calculating amino acid propensities, it was found that the proportion of secondary structures with respect to residue depth is directly related to their hydrophobicity. As for dynamic feature, normal mode analysis (NMA) based on an elastic network model (ENM) was carried out for the dataset using our KOSMOS web server (http://bioengineering.skku.ac.kr/kosmos/). All ENM-based NMA results were stored in the KOSMOS database, allowing researchers to use them in various ways. In this process, it was commonly found that high B-factors appeared at the edge of the alpha helix region, which was elucidated by introducing residue depth. In addition, by investigating the change in dihedral angle, it was possible to quantitatively survey the contribution of structural change of protein on the Ramachandran plot. In conclusion, our statistical analysis of protein characteristics will provide insight into a range of protein structural studies.

Understanding carbon nanotube channel formation in the lipid membrane.

Carbon nanotubes (CNTs) have been considered a prominent nano-channel in cell membranes because of their prominent ion-conductance and ion-selectivity, offering agents for a biomimetic channel platform. Using a coarse-grained molecular dynamics simulation, we clarify a construction mechanism of vertical CNT nano-channels in a lipid membrane for a long period, which has been difficult to observe in previous CNT-lipid interaction simulations. The result shows that both the lipid coating density and length of CNT affect the suitable fabrication condition for a vertical and stable CNT channel. Also, simulation elucidated that a lipid coating on the surface of the CNT prevents the CNT from burrowing into the lipid membrane and the vertical channel is stabilized by the repulsion force between the lipids in the coating and membrane. Our study provides an essential understanding of how CNTs can form stable and vertical channels in the membrane, which is important for designing new types of artificial channels as biosensors for bio-fluidic studies.

Fabrication and Characterization of Finite-Size DNA 2D Ring and 3D Buckyball Structures.

In order to incorporate functionalization into synthesized DNA nanostructures, enhance their production yield, and utilize them in various applications, it is necessary to study their physical stabilities and dynamic characteristics. Although simulation-based analysis used for DNA nanostructures provides important clues to explain their self-assembly mechanism, structural function, and intrinsic dynamic characteristics, few studies have focused on the simulation of DNA supramolecular structures due to the structural complexity and high computational cost. Here, we demonstrated the feasibility of using normal mode analysis for relatively complex DNA structures with larger molecular weights, i.e., finite-size DNA 2D rings and 3D buckyball structures. The normal mode analysis was carried out using the mass-weighted chemical elastic network model (MWCENM) and the symmetry-constrained elastic network model (SCENM), both of which are precise and efficient modeling methodologies. MWCENM considers both the weight of the nucleotides and the chemical bonds between atoms, and SCENM can obtain mode shapes of a whole structure by using only a repeated unit and its connectivity with neighboring units. Our results show the intrinsic vibrational features of DNA ring structures, which experience inner/outer circle and bridge motions, as well as DNA buckyball structures having overall breathing and local breathing motions. These could be used as the fundamental basis for designing and constructing more complicated DNA nanostructures.

Robust elastic network model: A general modeling for precise understanding of protein dynamics.

In the study of protein dynamics relevant to functions, normal mode analysis based on elastic network models (ENMs) has become popular. These models are usually validated by comparing the calculated atomic fluctuation for a single protein in a vacuum to experimental temperature factors in the crystal packing state. Without reflecting the crystal packing effect, in addition, their arbitrary assignment of spring constants leads to inaccurate simulation results, yielding a low correlation of the B-factor. To overcome this limitation, we propose a robust elastic network model (RENM) that not only considers the crystalline effect by using symmetric constraint information but also uses lumped masses and specific spring constants based on the type of amino acids and chemical interactions, respectively. Simulation results with more than 500 protein structures verify qualitatively and quantitatively that one can obtain the better correlation of the B-factor by RENM without additional computational burden. Moreover, an optimal spring constant in physical units (dyne/cm) is quantitatively determined as a function of the temperature at 100 and 290K, which enables us to predict the atomic fluctuations and vibrational density of states (VDOS) without a fitting process. The additional investigation of 80 high-resolution crystal structures with anisotropic displacement parameters (ADPs) indicates that RENM could give a full description of vibrational characteristics of individual residues in proteins.

Ternary and senary representations using DNA double-crossover tiles.

The information capacity of DNA double-crossover (DX) tiles was successfully increased beyond a binary representation to higher base representations. By controlling the length and the position of DNA hairpins on the DX tile, ternary and senary (base-3 and base-6) digit representations were realized and verified by atomic force microscopy. Also, normal mode analysis was carried out to study the mechanical characteristics of each structure.

Vibrational characteristics of graphene sheets elucidated using an elastic network model.

Recent studies of graphene have demonstrated its great potential for highly sensitive resonators. In order to capture the intrinsic vibrational characteristics of graphene, we propose an atomistic modeling method called the elastic network model (ENM), in which a graphene sheet is modeled as a mass-spring network of adjacent atoms connected by various linear springs with specific bond ratios. Normal mode analysis (NMA) reveals the various vibrational features of bi-layer graphene sheets (BLGSs) clamped at two edges. We also propose a coarse-graining (CG) method to extend our graphene study into the meso- and macroscales, at which experimental measurements and synthesis of graphene become practical. The simulation results show good agreement with experimental observations. Therefore, the proposed ENM approach will not only shed light on the theoretical study of graphene mechanics, but also play an important role in the design of highly-sensitive graphene-based resonators.

KOSMOS: a universal morph server for nucleic acids, proteins and their complexes.

KOSMOS is the first online morph server to be able to address the structural dynamics of DNA/RNA, proteins and even their complexes, such as ribosomes. The key functions of KOSMOS are the harmonic and anharmonic analyses of macromolecules. In the harmonic analysis, normal mode analysis (NMA) based on an elastic network model (ENM) is performed, yielding vibrational modes and B-factor calculations, which provide insight into the potential biological functions of macromolecules based on their structural features. Anharmonic analysis involving elastic network interpolation (ENI) is used to generate plausible transition pathways between two given conformations by optimizing a topology-oriented cost function that guarantees a smooth transition without steric clashes. The quality of the computed pathways is evaluated based on their various facets, including topology, energy cost and compatibility with the NMA results. There are also two unique features of KOSMOS that distinguish it from other morph servers: (i) the versatility in the coarse-graining methods and (ii) the various connection rules in the ENM. The models enable us to analyze macromolecular dynamics with the maximum degrees of freedom by combining a variety of ENMs from full-atom to coarse-grained, backbone and hybrid models with one connection rule, such as distance-cutoff, number-cutoff or chemical-cutoff. KOSMOS is available at http://bioengineering.skku.ac.kr/kosmos.

Solid-state thermal rectification of bilayers by asymmetric elastic modulus.

A highly efficient thermal rectification applicable to large panels still needs to be developed. Here, we experimentally achieve a high thermal rectification efficiency of 33% by carefully engineering elastic modulus asymmetry in a centimeter-scale bilayered silver-graphene oxide sponge. The thermal conduction primarily occurs in the out-of-plane direction, and the forward heat flow direction is from the hard silver to the soft graphene oxide. Surprisingly, the forward heat flow direction is reversed when a silver layer is formed on a harder polystyrene foam. The forward direction is always from the harder side to the softer side, and the asymmetry in elastic modulus is suggested as a possible mechanism based on the one-dimensional Frenkel-Kontorova (FK) model. The finite element analysis indicates that other mechanisms such as temperature-dependent thermal conductivity and radiation asymmetry cannot explain the high rectification efficiency. This scalable work over a wide temperature range may find immediate industrial applications.

DNA nanotube formation based on normal mode analysis.

Ever since its inception, a popular DNA motif called the cross tile has been recognized to self-assemble into addressable 2D templates consisting of periodic square cavities. Although this may be conceptually correct, in reality certain types of cross tiles can only form planar lattices if adjacent tiles are designed to bind in a corrugated manner, in the absence of which they roll up to form 3D nanotube structures. Here we present a theoretical study on why uncorrugated cross tiles self-assemble into counterintuitive 3D nanotube structures and not planar 2D lattices. Coarse-grained normal mode analysis of single and multiple cross tiles within the elastic network model was carried out to expound the vibration modes of the systems. While both single and multiple cross tile simulations produce results conducive to tube formations, the dominant modes of a unit of four cross tiles (one square cavity), termed a quadruplet, fully reflect the symmetries of the actual nanotubes found in experiments and firmly endorse circularization of an array of cross tiles.

Raman Scattering Measurement of Suspended Graphene under Extreme Strain Induced by Nanoindentation.

Graphene is known as a superstiff and extremely strong material. Hence, applying strains greater than 1% to graphene and simultaneously measuring changes in its physical properties has been challenging because of the limited methodologies for measuring both high strain and other physical properties. Here, Raman scattering measurement of suspended graphene under extremely high biaxial strain as large as 6.1% using an atomic force microscopy (AFM)-Raman spectroscopy measurement tool is reported. Nanoindentation is performed using AFM tips machined to have a flat top and a hole shape, resulting in a strained graphene area sufficiently large to enable the acquisition of a Raman signal. At the same time, the laser light is focused on the strained flat area of the graphene membrane. The Raman signals of the G and 2D bands of graphene are redshifted by 282 and 684 cm-1 , respectively, which is unprecedented for graphene. This measurement technique provides an effective methodology to measure variations in the physical properties of atomically thin materials under superhigh strain.

Intrinsic DNA curvature of double-crossover tiles.

A theoretical model which takes into account the structural distortion of double-crossover DNA tiles has been studied to investigate its effect on lattice formation sizes. It has been found that a single vector appropriately describes the curvature of the tiles, of which a higher magnitude hinders lattice growth. In conjunction with these calculations, normal mode analysis reveals that tiles with relative higher frequencies have an analogous effect. All the theoretical results are shown to be in good agreement with experimental data.

Prediction of anisotropic behavior of nano/micro composite based on damage mechanics with cell modeling.

New advanced composite materials have recently been of great interest. Especially, many researchers have studied on nano/micro composites based on matrix filled with nano-particles, nano-tubes, nano-wires and so forth, which have outstanding characteristics on thermal, electrical, optical, chemical and mechanical properties. Therefore, the need of numerical approach for design and development of the advanced materials has been recognized. In this paper, finite element analysis based on multi-resolution continuum theory is carried out to predict the anisotropic behavior of nano/micro composites based on damage mechanics with a cell modeling. The cell modeling systematically evaluates constitutive relationships from microstructure of the composite material. Effects of plastic anisotropy on deformation behavior and damage evolution of nano/micro composite are investigated by using Hill's 48 yield function and also compared with those obtained from Gurson-Tvergaard-Needleman isotropic damage model based on von Mises yield function.

Protein conformational transitions explored by a morphing approach based on normal mode analysis in internal coordinates.

Large-scale conformational changes are essential for proteins to function properly. Given that these transition events rarely occur, however, it is challenging to comprehend their underlying mechanisms through experimental and theoretical approaches. In this study, we propose a new computational methodology called internal coordinate normal mode-guided elastic network interpolation (ICONGENI) to predict conformational transition pathways in proteins. Its basic approach is to sample intermediate conformations by interpolating the interatomic distance between two end-point conformations with the degrees of freedom constrained by the low-frequency dynamics afforded by normal mode analysis in internal coordinates. For validation of ICONGENI, it is applied to proteins that undergo open-closed transitions, and the simulation results (i.e., simulated transition pathways) are compared with those of another technique, to demonstrate that ICONGENI can explore highly reliable pathways in terms of thermal and chemical stability. Furthermore, we generate an ensemble of transition pathways through ICONGENI and investigate the possibility of using this method to reveal the transition mechanisms even when there are unknown metastable states on rough energy landscapes.

Selective HDAC8 Inhibition Attenuates Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis via p38 MAPK Pathway.

Histone deacetylase (HDAC) expression and enzymatic activity are dysregulated in cardiovascular diseases. Among Class I HDACs, HDAC2 has been reported to play a key role in cardiac hypertrophy; however, the exact function of HDAC8 remains unknown. Here we investigated the role of HDAC8 in cardiac hypertrophy and fibrosis using the isoproterenol-induced cardiac hypertrophy model system.Isoproterenol-infused mice were injected with the HDAC8 selective inhibitor PCI34051 (30 mg kg-1 body weight). Enlarged hearts were assessed by HW/BW ratio, cross-sectional area, and echocardiography. RT-PCR, western blotting, histological analysis, and cell size measurements were performed. To elucidate the role of HDAC8 in cardiac hypertrophy, HDAC8 knockdown and HDAC8 overexpression were also used. Isoproterenol induced HDAC8 mRNA and protein expression in mice and H9c2 cells, while PCI34051 treatment decreased cardiac hypertrophy in isoproterenol-treated mice and H9c2 cells. PCI34051 treatment also reduced the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), transcription factors (Sp1, Gata4, and Gata6), and fibrosis markers (collagen type I, fibronectin, and Ctgf) in isoproterenol-treated mice. HDAC8 overexpression stimulated cardiac hypertrophy in cells, whereas HDAC8 knockdown reversed those effects. HDAC8 selective inhibitor and HDAC8 knockdown reduced the isoproterenol-induced activation of p38 MAPK, whereas HDAC8 overexpression promoted p38 MAPK phosphorylation. Furthermore, p38 MAPK inhibitor SB203580 significantly decreased the levels of p38 MAPK phosphorylation, as well as ANP and BNP protein expression, induced by HDAC8 overexpression.Here we show that inhibition of HDAC8 activity or expression suppresses cardiac hypertrophy and fibrosis. These findings suggest that HDAC8 could be a promising target to treat cardiac hypertrophy and fibrosis by regulating p38 MAPK.

Effects of aquaporin-lipid molar ratio on the permeability of an aquaporin Z-phospholipid membrane system.

Aquaporins are water-permeable membrane-channel proteins found in biological cell membranes that selectively exclude ions and large molecules and have high water permeability, which makes them promising candidates for water desalination systems. To effectively apply the properties of aquaporins in the desalination process, many studies have been conducted on aquaporin-lipid membrane systems using phospholipids, which are the main component of cell membranes. Many parametric studies have evaluated the permeability of such systems with various aquaporin types and lipid compositions. In this study, we performed molecular dynamics simulations for four cases with different protein-lipid molar ratios (1:50, 1:75, 1:100, and 1:150) between aquaporin Z and the phospholipids, and we propose a possibility of the existence of optimal protein-lipid molar ratio to maximize water permeability. Elucidating these simulation results from a structural viewpoint suggests that there is a relationship between the permeability and changes in the hydrophobic thickness of the lipid membrane adjacent to the aquaporin as a structural parameter. The results of this study can help optimize the design of an aquaporin-lipid membrane by considering its molar ratio at an early stage of development.

Electron tunneling of hierarchically structured silver nanosatellite particles for highly conductive healable nanocomposites.

Healable conductive materials have received considerable attention. However, their practical applications are impeded by low electrical conductivity and irreversible degradation after breaking/healing cycles. Here we report a highly conductive completely reversible electron tunneling-assisted percolation network of silver nanosatellite particles for putty-like moldable and healable nanocomposites. The densely and uniformly distributed silver nanosatellite particles with a bimodal size distribution are generated by the radical and reactive oxygen species-mediated vigorous etching and reduction reaction of silver flakes using tetrahydrofuran peroxide in a silicone rubber matrix. The close work function match between silicone and silver enables electron tunneling between nanosatellite particles, increasing electrical conductivity by ~5 orders of magnitude (1.02×103 Scm-1) without coalescence of fillers. This results in ~100% electrical healing efficiency after 1000 breaking/healing cycles and stability under water immersion and 6-month exposure to ambient air. The highly conductive moldable nanocomposite may find applications in improvising and healing electrical parts.

Temperature and strain discrimination based on a temperature-insensitive birefringent interferometer incorporating an erbium-doped fiber.

A simple configuration for simultaneous measurement of temperature and strain exploiting a temperature-insensitive birefringent interferometer based on a photonic crystal fiber incorporating an erbium-doped fiber (EDF) is investigated. The transmission peak power of the birefringent interferometer incorporating the EDF is changed by the temperature variation because the amplified spontaneous emission of the EDF strongly depends on temperature. The applied strain changes the peak wavelength of the birefringent interferometer connecting with the EDF, which can make it possible to discriminate concurrent sensitivities like temperature and strain. The temperature and strain sensitivities were -0.04 dB/ degrees C and 1.3 pm/microepsilon, respectively.

Characterization of FBG sensor interrogation based on a FDML wavelength swept laser.

In this study, we develop an ultra-fast fiber Bragg grating sensor system that is based on the Fourier domain mode-locked (FDML) swept laser. A FDML wavelength swept laser has many advantages compared to the conventional wavelength swept laser source, such as high-speed interrogation, narrow spectral sensitivity, and high phase stability. The newly developed FDML wavelength swept laser shows a superior performance of a high scan rate of 31.3 kHz and a broad scan range of over 70 nm simultaneously. The performance of the grating sensor interrogating system using a FDML wavelength swept laser is characterized in both static and dynamic strain responses.

Spectrally-sampled OCT for sensitivity improvement from limited optical power.

Although high optical illumination power is favored in optical coherence tomography (OCT) for better signal-to-noise ratio, optical power is often limited by a damaged threshold for biomedical living tissues and autocorrelation signals observed in tomograms. In order to improve signal sensitivity without increasing the optical illumination power, a spectrally sampled multi-wavelength light source is proposed for the OCT system. A fiber Sagnac comb filter was used to spectrally sample the output of a continuous spectral light source. Point spread function analysis shows that the spectrally sampled OCT has an almost 50% dynamic range improvement in comparison with a conventional continuous spectral light source OCT for the same average optical power of 6 mW.

Facilitated Water Transport through Graphene Oxide Membranes Functionalized with Aquaporin-Mimicking Peptides.

Water purification by membranes is widely investigated to address concerns related to the scarcity of clean water. Achieving high flux and rejection simultaneously is a difficult challenge using such membranes because these properties are mutually exclusive in common artificial membranes. Nature has developed a method for this task involving water-channel membrane proteins known as aquaporins. Here, the design and fabrication of graphene oxide (GO)-based membranes with a surface-tethered peptide motif designed to mimic the water-selective filter of natural aquaporins is reported. The short RF8 (RFRFRFRF, where R and F represent arginine and phenylalanine, respectively) octapeptide is a concentrated form of the core component of the Ar/R (aromatic/arginine) water-selective filter in aquaporin. The resulting GO-RF8 shows superior flux and high rejection similar to natural aquaporins. Molecular dynamics simulation reveal the unique configuration of RF8 peptides and the transport of water in GO-RF8 membranes, supporting that RF8 effectively emulates the core function of aquaporins.