Structural Dynamics Research Articles

Editorial to special issue “Recent mechanics-based developments in structural dynamics and earthquake engineering”

Editorial to special issue “Recent mechanics-based developments in structural dynamics and earthquake engineering”

Titin: The Missing Link in Cardiac Physiology

Titin, an extraordinary protein known for its colossal size and multifaceted roles, is a cornerstone in the structural and functional dynamics of striated muscle tissues, including the heart and skeletal muscles. Its sheer enormity, with a molecular weight exceeding 3000 kDa, is paralleled only by the immense influence it exerts on muscle physiology. This review will delve into the remarkable structural organization of Titin and the genetics of this molecule, including the common mutations resulting in various cardiomyopathies. We will delve deeper into its role in dilated cardiomyopathy, familial restrictive cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction cardiomyopathy. This review culminates by discussing the prospects of therapeutic strategies targeting Titin. While these interventions remain primarily theoretical, the possibilities are intriguing. Patients with Titin truncation mutations present unique challenges, but innovative approaches like gene therapy or preemptive treatments with drugs such as angiotensin-converting enzyme inhibitors or beta-blockers offer hope. This multi-pronged approach highlights the significance of understanding Titin’s multifaceted role and its potential as a target for future therapeutic interventions.

Evaluating Mass Spectrometry-Based Hydroxyl Radical Protein Footprinting of a Benchtop Flash Oxidation System against a Synchrotron X-ray Beamline.

Hydroxyl radical protein footprinting (HRPF) using synchrotron X-ray radiation (XFP) and mass spectrometry is a well-validated structural biology method that provides critical insights into macromolecular structural dynamics, such as determining binding sites, measuring affinity, and mapping epitopes. Numerous alternative sources for generating the hydroxyl radicals (•OH) needed for HRPF, such as laser photolysis and plasma irradiation, complement synchrotron-based HRPF, and a recently developed commercially available instrument based on flash lamp photolysis, the FOX system, enables access to laboratory benchtop HRPF. Here, we evaluate performing HRPF experiments in-house with a benchtop FOX instrument compared to synchrotron-based X-ray footprinting at the NSLS-II XFP beamline. Using lactate oxidase (LOx) as a model system, we carried out •OH labeling experiments using both instruments, followed by nanoLC-MS/MS bottom-up peptide mass mapping. Experiments were performed under high glucose concentrations to mimic the highly scavenging conditions present in biological buffers and human clinical samples, where less •OH are available for reaction with the biomolecule(s) of interest. The performance of the FOX and XFP HRPF methods was compared, and we found that tuning the •OH dosage enabled optimal labeling coverage for both setups under physiologically relevant highly scavenging conditions. Our study demonstrates the complementarity of FOX and XFP labeling approaches, demonstrating that benchtop instruments such as the FOX photolysis system can increase both the throughput and the accessibility of the HRPF technique.

Theoretical study of structural phase transition and soft mode behavior in moganite

Changes in the structure and lattice dynamics of the moganite during crystal expansion were studiedusing ab initio calculations within the framework of density functional theory. The results obtained shed light onmany anomalies in the temperature behavior of this crystal, such as the presence of a phase transition, soft modecondensation, elastic anomalies and negative thermal expansion. Comparison of the structural and dynamicproperties of moganite and quartz opens up new possibilities for their identification in natural samples of mixedcomposition.

Evolving precision: rRNA expansion segment 7S modulates translation velocity and accuracy in eukaryal ribosomes.

Ribosome-enhancedtranslational miscoding of the genetic code causes protein dysfunction and loss of cellular fitness. During evolution, open reading frame length increased, necessitating mechanisms for enhanced translation fidelity. Indeed, eukaryal ribosomes are more accurate than bacterial counterparts, despite their virtually identical, conserved active centers. During the evolution of eukaryotic organisms ribosome expansions at the rRNA and protein level occurred, which potentially increases the options for translation regulation and cotranslational events. Here we tested the hypothesis that ribosomal RNA expansions can modulate the core function of the ribosome, faithful protein synthesis. We demonstrate that a short expansion segment present in all eukaryotes' small subunit, ES7S, is crucial for accurate protein synthesis as its presence adjusts codon-specific velocities and guarantees high levels of cognate tRNA selection. Deletion of ES7S in yeast enhances mistranslation and causes protein destabilization and aggregation, dramatically reducing cellular fitness. Removal of ES7S did not alter ribosome architecture but altered the structural dynamics of inter-subunit bridges thus affecting A-tRNA selection. Exchanging the yeast ES7S sequence with the human ES7S increases accuracy whereas shortening causes the opposite effect. Our study demonstrates that ES7S provided eukaryal ribosomes with higher accuracy without perturbing the structurally conserved decoding center.

Expression and Purification of Cp3GT: Structural Analysis and Modeling of a Key Plant Flavonol-3-O Glucosyltransferase from Citrus paradisi.

Glycosyltransferases (GTs) are pivotal enzymes in the biosynthesis of various biological molecules. This study focuses on the scale-up, expression, and purification of a plant flavonol-specific 3-O glucosyltransferase (Cp3GT), a key enzyme from Citrus paradisi, for structural analysis and modeling. The challenges associated with recombinant protein production in Pichia pastoris, such as proteolytic degradation, were addressed through the optimization of culture conditions and purification processes. The purification strategy employed affinity, anion exchange, and size exclusion chromatography, leading to greater than 95% homogeneity for Cp3GT. In silico modeling, using D-I-TASSER and COFACTOR integrated with the AlphaFold2 pipeline, provided insights into the structural dynamics of Cp3GT and its ligand binding sites, offering predictions for enzyme-substrate interactions. These models were compared to experimentally derived structures, enhancing understanding of the enzyme's functional mechanisms. The findings present a comprehensive approach to produce a highly purified Cp3GT which is suitable for crystallographic studies and to shed light on the structural basis of flavonol specificity in plant GTs. The significant implications of these results for synthetic biology and enzyme engineering in pharmaceutical applications are also considered.

Improving Low-Frequency Panel Absorbers with Two-Dimensional Acoustic Black Hole

Many rooms struggle with the absorption of low-frequency sound due to its long wavelengths. The integration of existing solutions into these spaces is often challenging due to their intricate installations and large depths. To address this problem, a new type of resonance absorber has been developed: the Distributed Mode Absorber (DMA). It consists of a thin vibrating front panel and a volume of enclosed air behind it. This straightforward structure can be utilized to create acoustically functional furniture that can be seamlessly incorporated into rooms. This article is devoted to the structural optimization of the DMA front panel, using the Acoustic Black Hole (ABH) effect known within structural dynamics. A numerical model is constructed using a Finite Element Analysis (FEA) and examined numerically. Several geometric parameters of the ABH are studied with regard to their influence on the vibrations of the front panel. Prototypes are developed and manufactured based on these insights. The quality of the numerical model is verified during the subsequent validation. Finally, the sound absorption of the improved DMA is compared with that of the reference DMA.

Tumor-acquired somatic mutation affects conformation to abolish ABCG2-mediated drug resistance

ABCG2 is an important ATP-binding cassette transporter impacting the absorption and distribution of over 200 chemical toxins and drugs. ABCG2 also reduces the cellular accumulation of diverse chemotherapeutic agents. Acquired somatic mutations in the phylogenetically conserved amino acids of ABCG2 might provide unique insights into its molecular mechanisms of transport. Here, we identify a tumor-derived somatic mutation (Q393K) that occurs in a highly conserved amino acid across mammalian species. This ABCG2 mutant seems incapable of providing ABCG2-mediated drug resistance. This was perplexing because it is localized properly and retained interaction with substrates and nucleotides. Using a conformationally sensitive antibody, we show that this mutant appears “locked” in a non-functional conformation. Structural modeling and molecular dynamics simulations based on ABCG2 cryo-EM structures suggested that the Q393K interacts with the E446 to create a strong salt bridge. The salt bridge is proposed to stabilize the inward-facing conformation, resulting in an impaired transporter that lacks the flexibility to readily change conformation, thereby disrupting the necessary communication between substrate binding and transport.

Metabolite fingerprinting and profiling of two locally cultivated edible plants by using nuclear magnetic resonance

Nuclear magnetic resonance (NMR) spectroscopy is a sensitive technique used to analyse the structure elucidation, dynamics, reaction state, and chemical environment of molecules. Abelmoschus esculentus and Lagenaria siceraria are edible plants used traditionally to treat jaundice, diabetes, weight loss, ulcer, hypertension, heart failure, skin diseases and reduced cholesterol. Therefore, based on the medicinal uses the study was designed to analyze fingerprinting of metabolites of the seeds of the selected plants. The dry seeds were powdered and the metabolites were extracted by socking method with a mixture of methanol/chloroform. The extracted metabolites from seeds were subjected to proton NMR using the noesygpprld pulse sequence. A total 18 peaks were obtained from each spectrum. Among the peaks, three peaks with the highest intensities were analyzed by utilizing NMR. The peak metabolites were determined with the correlation with the correct peak using in built Biological Magnetic Resonance Data Bank (BMRB). The results showed that the obtained data varied from known plant metabolites due to the contamination and interaction between the metabolites. In addition, variants in the metabolites from sample to sample may have been the result of errors or limitations in the study. The data generated from this experiment will be used to help to conduct the advanced research in the near future on the selected edible plant species which will be valuable for many different areas of the scientific community. Plant metabolomics has the potential benefit in the medical field, agricultural industry, and many other areas of our economy.

Extension of a sharp-interface immersed-boundary method for simulating parachute inflation

In this work, the sharp-interface immersed boundary (IB) method proposed by Mittal et al. (J Comput Phys 227(10):4825–4852, 2008) is extended to fluid-structure-interaction (FSI) simulation of parachute inflation by utilizing several open-source tools. The method employs a Cartesian-grid ghost-cell methodology to accurately represent the immersed boundary, and it is suitable for solving moving-boundary flows with arbitrarily complex geometries. The finite-element code CalculiX is employed to solve the structural dynamics of the parachute system. The IB flow solver is coupled with CalculiX in a minimally-invasive manner using the multi-physics coupling library preCICE. The implicit fluid-structure coupling together with the Aitken adaptive under-relaxation scheme is considered to improve the numerical accuracy and stability. The developed approach is validated by a benchmark FSI case. Numerical experiments on the inflation process of several typical parachutes are further conducted. The breathing process, flow structure, canopy displacement and drag coefficient are analyzed to demonstrate the applicability of the present approach for simulating parachute inflation.

Unravelling the amorphous structure and crystallization mechanism of GeTe phase change memory materials

The reversible phase transitions in phase-change memory devices can switch on the order of nanoseconds, suggesting a close structural resemblance between the amorphous and crystalline phases. Despite this, the link between crystalline and amorphous tellurides is not fully understood nor quantified. Here we use in-situ high-temperature x-ray absorption spectroscopy (XAS) and theoretical calculations to quantify the amorphous structure of bulk and nanoscale GeTe. Based on XAS experiments, we develop a theoretical model of the amorphous GeTe structure, consisting of a disordered fcc-type Te sublattice and randomly arranged chains of Ge atoms in a tetrahedral coordination. Strikingly, our intuitive and scalable model provides an accurate description of the structural dynamics in phase-change memory materials, observed experimentally. Specifically, we present a detailed crystallization mechanism through the formation of an intermediate, partially stable ‘ideal glass’ state and demonstrate differences between bulk and nanoscale GeTe leading to size-dependent crystallization temperature.

Microsecond dynamics control the HIV-1 Envelope conformation.

The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 μs, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design.

Effect of macromolecular crowding in the structural dynamics and druggability of a cryptic pocket in Ebola VP35

Effect of macromolecular crowding in the structural dynamics and druggability of a cryptic pocket in Ebola VP35

Structural dynamics in RhoGEF signaling investigated using model cell membranes

Structural dynamics in RhoGEF signaling investigated using model cell membranes

Structural dynamics at cytosolic inter-protomer interfaces control gating of a mammalian TRPM5 channel

Structural dynamics at cytosolic inter-protomer interfaces control gating of a mammalian TRPM5 channel

Trajectories and tipping points of piñon-juniper woodlands after fire and thinning.

Piñon-juniper (PJ) woodlands are a dominant community type across the Intermountain West, comprising over a million acres and experiencing critical effects from increasing wildfire. Large PJ mortality and regeneration failure after catastrophic wildfire have elevated concerns about the long-term viability of PJ woodlands. Thinning is increasingly used to safeguard forests from fire and in an attempt to increase climate resilience. We have only a limited understanding of how fire and thinning will affect the structure and function of PJ ecosystems. Here, we examined vegetation structure, microclimate conditions, and PJ regeneration dynamics following ~20 years post-fire and thinning treatments. We found that burned areas had undergone a state shift that did not show signs of returning to their previous state. This shift was characterized by (1) distinct plant community composition dominated by grasses; (2) a lack of PJ recruitment; (3) a decrease in the sizes of interspaces in between plants; (4) lower abundance of late successional biological soil crusts; (5) lower mean and minimum daily soil moisture values; (6) lower minimum daily vapor pressure deficit; and (7) higher photosynthetically active radiation. Thinning created distinct plant communities and served as an intermediate between intact and burned communities. More intensive thinning decreased PJ recruitment and late successional biocrust cover. Our results indicate that fire has the potential to create drier and more stressful microsite conditions, and that, in the absence of active management following fire, there may be shifts to persistent ecological states dominated by grasses. Additionally, more intensive thinning had a larger impact on community structure and recruitment than less intensive thinning, suggesting that careful consideration of goals could help avoid unintended consequences. While our results indicate the vulnerability of PJ ecosystems to fire, they also highlight management actions that could be adapted to create conditions that promote PJ re-establishment.

Structural insights into an actinobacteriophage capsid: Unveiling the prolate head structure and C-terminal extension domain dynamics through cryo-EM and molecular dynamics simulations

Structural insights into an actinobacteriophage capsid: Unveiling the prolate head structure and C-terminal extension domain dynamics through cryo-EM and molecular dynamics simulations

Computer-Aided Rational Design Strategy to Improve the Thermal Stability of Alginate Lyase AlyMc.

Alginate lyase degrades alginate by the β-elimination mechanism to produce unsaturated alginate oligosaccharides (UAOS), which have better bioactivities than saturated AOS. Enhancing the thermal stability of alginate lyases is crucial for their industrial applications. In this study, a feasible and efficient rational design strategy was proposed by combining the computer-aided ΔΔG value calculation with the B-factor analysis. Two thermal stability-enhanced mutants, Q246V and K249V, were obtained by site-directed mutagenesis. Particularly, the t1/2,50°C for mutants Q246V and K249V was increased from 2.36 to 3.85 and 3.65 h, respectively. Remarkably, the specific activities of Q246V and K249V were enhanced to 2.41- and 2.96-fold that of alginate lyase AlyMc, respectively. Structural analysis and molecular dynamics simulations suggested that mutations enhanced the hydrogen bond networks and the overall rigidity of the molecular structure. Notably, mutant Q246V exhibited excellent thermal stability among the PL-7 alginate lyase family, especially considering the heightened enzymatic activity. Moreover, the rational design strategy used in this study can effectively improve the thermal stability of enzymes and has important significance in advancing applications of alginate lyase.

Breaking reflection symmetry: evolving long dynamical cycles in Boolean systems

In interacting dynamical systems, specific local interaction rules for system components give rise to diverse and complex global dynamics. Long dynamical cycles are a key feature of many natural interacting systems, especially in biology. Examples of dynamical cycles range from circadian rhythms regulating sleep to cell cycles regulating reproductive behavior. Despite the crucial role of cycles in nature, the properties of network structure that give rise to cycles still need to be better understood. Here, we use a Boolean interaction network model to study the relationships between network structure and cyclic dynamics. We identify particular structural motifs that support cycles, and other motifs that suppress them. More generally, we show that the presence of dynamical reflection symmetry in the interaction network enhances cyclic behavior. In simulating an artificial evolutionary process, we find that motifs that break reflection symmetry are discarded. We further show that dynamical reflection symmetries are over-represented in Boolean models of natural biological systems. Altogether, our results demonstrate a link between symmetry and functionality for interacting dynamical systems, and they provide evidence for symmetry’s causal role in evolving dynamical functionality.

The AGORA High-resolution Galaxy Simulations Comparison Project. VI. Similarities and Differences in the Circumgalactic Medium

We analyze the circumgalactic medium (CGM) for eight commonly-used cosmological codes in the AGORA collaboration. The codes are calibrated to use identical initial conditions, cosmology, heating and cooling, and star formation thresholds, but each evolves with its own unique code architecture and stellar feedback implementation. Here, we analyze the results of these simulations in terms of the structure, composition, and phase dynamics of the CGM. We show properties such as metal distribution, ionization levels, and kinematics are effective tracers of the effects of the different code feedback and implementation methods, and as such they can be highly divergent between simulations. This is merely a fiducial set of models, against which we will in the future compare multiple feedback recipes for each code. Nevertheless, we find that the large parameter space these simulations establish can help disentangle the different variables that affect observable quantities in the CGM, e.g., showing that abundances for ions with higher ionization energy are more strongly determined by the simulation’s metallicity, while abundances for ions with lower ionization energy are more strongly determined by the gas density and temperature.