Normal Mode Analysis Research Articles

Coarse-Grained Models for Vault Normal Model Analysis.

Recent experiments have shown that the molecular complex of vault has large conformational changes at its shoulder and cap regions in solution. From the comparison of two configuration structures, it has been found that the shoulder region can twist and move outward, while the cap region will rotate and push upward correspondingly. To further understand these experimental results, in this paper, we study the vault dynamics for the first time. Since vault has an extremely large-sized structure with around 63,336 Cα atoms, traditional normal mode method with the Cα coarse-grained representation will fall short. We employ a newly invented multiscale virtual particle-based anisotropic network model (MVP-ANM). To reduce the complexity, the 39-folder vault structure is coarse-grained to about 6000 virtual particles, which significantly reduces the computational cost while still maintaining the basic structure information. Among the 14 low frequency eigenmodes from Mode 7 to Mode 20, two eigenmodes, i.e., Mode 9 and Mode 20, are found to be directly associated with the experimental observations. In Mode 9, shoulder region undergoes a significant expansion while the cap part is lifted upward. In Mode 20, a clear rotation of both shoulder and cap regions is well observed. Our results are consistent with the experimental observations. More importantly, these low frequency eigenmodes indicate that the vault waist, shoulder and lower cap regions are the most likely regions for the opening of the vault particle. And the opening mechanism is highly likely to be rotation and expansion at these regions. As far as we know, this is the first work to provide the normal mode analysis for the vault complex.

The First Snake Venom KTS/Disintegrins-Integrin Interactions Using Bioinformatics Approaches.

Snake venom contains a number of active molecules that have been shown to possess high anti-tumor activities; disintegrins are an excellent example among these. Their ability to interact and bind with integrins suggests that they could be very valuable molecules for the development of new cancer therapeutic approaches. However, in the absence of a clear Lysine-Threonine-Serine (KTS) Disintegrins Integrin interaction model, the exact compound features behind it are still unknown. In this study, we investigated the structural characteristics of three KTS-disintegrins and the interaction mechanisms with the α1β1 integrin receptor using in silico bioinformatics approaches. Normal mode analysis showed that the flexibility of the KTSR motif and the C-terminal region play a key role and influence the KTS-Disintegrin-integrin interaction. Protein-protein docking also suggested that the interaction involving the KTSR motif is highly dependent on the residue following K21, S23 and R24. These findings contribute to a better understanding of the KTS-Disintegrin-Integrin structural differences and their interactions with α1β1 receptors, which could improve the selection process of the best active molecules for antitumor therapies.

Normal modes of Proca fields in AdS spacetime

A normal mode analysis for Proca fields in the anti-de Sitter (AdS) spacetime is given. It is found that the equations for the Proca field can be decoupled analytically. This is performed by changing the basis of the vector spherical harmonics decomposition. The normal modes and the normal mode frequencies of the Proca equation in the AdS spacetime are then analytically determined. It is also shown that the Maxwell field can be recovered by taking the massless limit of the Proca field with care so that the nonphysical gauge modes are eliminated.

Modeling of a homogeneous isotropic half space in the context of multi-phase lag coupled thermoelasticity

A two-dimensional multi-phase lag model in the context of generalized thermoelasticity is established for an isotropic half-space medium. A vector-matrix differential equation is obtained from the governing equations using normal mode analysis. The eigenvalue approach is applied to obtain the solutions. The temperature-dependent displacements, stresses, strains are calculated numerically and represented graphically to show the accuracy of the solution under mechanical and thermal loads.

Scytonemin redox status in a filamentous cyanobacterium visualized by an excitation-laser-line-scanning spontaneous Raman scattering spectral microscope

Some cyanobacteria produce a UVA-absorbing pigment, scytonemin, at extracellular sheaths. Although scytonemin-containing dark sheaths are recognizable through optical microscopes and its redox changes have been known for decades, there has been no report to obtain images of both oxidized and reduced scytonemins at subcellular resolution. Here, we show that a spontaneous Raman scattering spectral microscopy based on an excitation-laser-line-scanning method unveil 3D subcellular distributions of both the oxidized and reduced scytonemins in a filamentous cyanobacterium. The redox changes of scytonemin were supported by comparison in the Raman spectra between the cyanobacterial cells, solid-state scytonemin and quantum chemical normal mode analysis. Distributions of carotenoids, phycobilins, and the two redox forms of scytonemin were simultaneously visualized with an excitation wavelength at 1064 nm that is virtually free from the optical screening by the dark sheaths. The redox differentiation of scytonemin will advance our understanding of the redox homeostasis and secretion mechanisms of individual cyanobacteria as well as microscopic chemical environments in various microbial communities. The line-scanning Raman microscopy based on the 1064 nm excitation is thus a promising tool for exploring hitherto unreported Raman spectral features and distribution of nonfluorescent molecules embedded below nontransparent layers for visible light, while avoiding interference by autofluorescence.

New formulation of the Navier–Stokes equations for liquid flows

Abstract For isothermal liquid flows, the condition of incompressibility provides a useful simplification for describing their mechanical properties. Nevertheless, it overlooks acoustic effects, and it provides the unpleasant shortcoming of infinite propagation speed of velocity perturbations, no matter the type of constitutive equation for the shear stresses is adopted. In this paper, we provide a derivation of a new formulation of the Navier–Stokes equations for liquid flows that overcomes the above issues. The pressure looses its ancillary status of mere gauge variable (or equivalently Lagrange multiplier of the incompressibility condition) enforcing the solenoidal nature of the velocity field, and attains the proper physical meaning of hydrodynamic field variable characterized by its own spatiotemporal evolution. From the experimental evidence of sound attenuation, related to the occurrence of a non-vanishing bulk viscosity, the evolution equation for pressure in out-of-equilibrium conditions is derived without introducing any adjustable parameters. The connection between compressibility and memory effects in the propagation of internal stresses is established. Normal mode analysis and some preliminary simulations are also discussed.

Investigation of The Potential Inhibitor Effects Of Lycorine On Sars-Cov-2 Main Protease (Mpro) Using Molecular Dynamics Simulations and MMPBSA

The main protease (Mpro or 3CLpro) plays important roles in viral replication and is one of attractive targets for drug development for SARS-CoV-2. In this study, we investigated the potential inhibitory effect of lycorine molecule as a ligand on SARS-CoV-2 using computational approaches. For this purpose, we conducted molecular docking and molecular dynamics simulations MM-PB(GB)SA analyses. The findings showed that the lycorine ligand was successfully docked with catalytic dyad (Cys145 and His41) of SARS-CoV-2 Mpro with binding affinity changing between -6.71 and -7.03 kcal mol-1. MMPB(GB)SA calculations resulted according to GB (Generalized Born) approach in a Gibbs free energy changing between -24.925-+01152 kcal/mol between lycorine and SARS-CoV-2 which is promising. PB (Poisson Boltzmann) approach gave less favorable energy (-2.610±0.2611 kcal mol-1). Thus, Entropy calculations from the normal mode analysis (ΔS) were performed and it supported GB approach and conducted -23.100±6.4635 kcal mol-1. These results showed lycorine has a druggable potential but the drug effect of lycorine on COVID-19 is limited and experimental studies should be done with pharmacokinetic modifications that increase the drug effect of lycorine.

Sequence-sensitive elastic network captures dynamical features necessary for miR-125a maturation.

The Elastic Network Contact Model (ENCoM) is a coarse-grained normal mode analysis (NMA) model unique in its all-atom sensitivity to the sequence of the studied macromolecule and thus to the effect of mutations. We adapted ENCoM to simulate the dynamics of ribonucleic acid (RNA) molecules, benchmarked its performance against other popular NMA models and used it to study the 3D structural dynamics of human microRNA miR-125a, leveraging high-throughput experimental maturation efficiency data of over 26 000 sequence variants. We also introduce a novel way of using dynamical information from NMA to train multivariate linear regression models, with the purpose of highlighting the most salient contributions of dynamics to function. ENCoM has a similar performance profile on RNA than on proteins when compared to the Anisotropic Network Model (ANM), the most widely used coarse-grained NMA model; it has the advantage on predicting large-scale motions while ANM performs better on B-factors prediction. A stringent benchmark from the miR-125a maturation dataset, in which the training set contains no sequence information in common with the testing set, reveals that ENCoM is the only tested model able to capture signal beyond the sequence. This ability translates to better predictive power on a second benchmark in which sequence features are shared between the train and test sets. When training the linear regression model using all available data, the dynamical features identified as necessary for miR-125a maturation point to known patterns but also offer new insights into the biogenesis of microRNAs. Our novel approach combining NMA with multivariate linear regression is generalizable to any macromolecule for which relatively high-throughput mutational data is available.

Bioinformatics and Network Pharmacology of the First Crystal Structured Clerodin: Anticancer and Antioxidant Potential against Human Breast Carcinoma Cell.

Clerodin was isolated from the medicinal plant Clerodendrum infortunatum, and CSD search showed the first crystal structure of clerodin by a single-crystal X-ray diffraction study. We checked its binding potential with target proteins by docking and conducted network pharmacology analysis, ADMET analysis, in silico pathway analysis, normal mode analysis (NMA), and cytotoxic activity studies to evaluate clerodin as a potential anticancer agent. The cell viability studies of clerodin on the human breast carcinoma cell line (MCF-7) showed toxicity on MCF-7 cells but no toxicity toward normal human lymphocyte cells (HLCs). The anticancer mechanism of clerodin was validated by its enhanced capacity to produce intracellular reactive oxygen species (ROS) and to lower the reduced glutathione content in MCF-7 cells.

The importance of localized modes spectral contribution to thermal conductivity in amorphous polymers

Polymers are a unique class of materials from the perspective of normal mode analysis. Polymers consist of individual chains with repeating units and strong intra-chain covalent bonds, and amorphous arrangements among chains with weak inter-chain van der Waals and for some polymers also electrostatic interactions. Intuitively, this strong heterogeneity in bond strength can give rise to special features in the constituent phonons, but such effects have not been studied deeply before. Here, we use lattice dynamics and molecular dynamics to perform modal analysis of the thermal conductivity in amorphous polymers. We find an abnormally large population of localized modes in amorphous polymers, which is fundamentally different from amorphous inorganic materials. Contrary to the common picture of thermal transport, localized modes in amorphous polymers are found to be the dominant contributors to thermal conductivity. We find that a significant portion of the localization happens within individual chains, but heat is dominantly conducted when localized modes involve two chains. These results suggest localized modes generally play a key role in thermal transport for different polymers. The results provide an alternative perspective on why polymer thermal conductivity is generally quite low and gives insight into how to potentially change it.

Thermosolutal Instability of Couple Stress Rivlin Ericksen Ferromagnetic Fluid with Rotation, Magnetic and Variable Gravity Field in Porous Medium

In this paper thermosolutal instability of a couple stress Rivlin-Ericksen ferromagnetic fluid layerwith rotation, magnetic and variable gravity field in porous medium is studied. Using normalmode analysis technique the dispersion relation has been obtained and solved analytically. Forstationary convention, it is found that couple stress, magnetic field and permeability of mediumhave stabilizing effect on thermal instability under certain conditions. Rotation has stabilizingeffect if λ> 0 and destabilizing effect if λ< 0. Solute gradients has stabilizing effect either λ >0 or λ < 0. The presence of solute gradient, viscoelastic parameter, rotation and magnetic fieldintroduces oscillatory modes, stability in the system and principle of exchange of stability is notsatisfied if λ < 0 and system may be stable or unstable if λ > 0.

Detailed Analysis of the Electromagnetic Normal Modes of Spherical and Annular Spherical Cavities: Energy, Thrust and Losses. Implications on the Spherical Casimir Effect

This paper develops analytical expressions of energy, thrust and losses for all electromagnetics normal modes in spherical and annular spherical cavities. The implications on the spherical Casimir effect are also investigated.

Nonlinear Rayleigh wave propagation in thermoelastic media in dual-phase-lag.

A model of generalized thermoelasticity within dual-phase-lag is used to investigate nonlinear Rayleigh wave propagation in a half-space of a transversely isotropic elastic material. It is assumed that the coefficient of heat conduction is temperature-dependent, a fact that plays an important role in the coupling behaviour analysis of thermoelastic and piezo-thermoelastic solids. Taking such a dependence into account becomes a necessity at higher temperatures and in nano-structures, when the material properties can no longer be considered as constants. Normal mode analysis is applied to find a particular solution to the problem under consideration. A concrete case is solved under prescribed boundary conditions and tentative values of the different material coefficients. The results are discussed to reveal the effect of temperature dependence of the heat conduction coefficient, as well as the thermal relaxation times, on nonlinear Rayleigh wave propagation. All quantities of practical interest are illustrated in two-and three-dimensional plots. The presented results may be useful in the detection of the second harmonic amplitudes through measurements related to the propagating heat wave.

Molecular modelling of the HCMV IL-10 protein isoforms and analysis of their interaction with the human IL-10 receptor.

The human cytomegalovirus (HCMV) UL111A gene encodes several homologs of the cellular interleukin 10 (cIL-10). Alternative splicing in the UL111A region produces two relatively well-characterized transcripts designated cmvIL-10 (isoform A) and LAcmvIL-10 (isoform B). The cmvIL-10 protein is the best characterized, both structurally and functionally, and has many immunosuppressive activities similar to cIL-10, while LAcmvIL-10 has more restricted biological activities. Alternative splicing also results in five less studied UL111A transcripts encoding additional proteins homologous to cIL-10 (isoforms C to G). These transcripts were identified during productive HCMV infection of MRC-5 cells with the high passage laboratory adapted AD169 strain, and the structure and properties of the corresponding proteins are largely unknown. Moreover, it is unclear whether these protein isoforms are able to bind the cellular IL-10 receptor and induce signalling. In the present study, we investigated the expression spectrum of UL111A transcripts in fully permissive MRC-5 cells and semi permissive U251 cells infected with the low passage HCMV strain TB40E. We identified a new spliced transcript (H) expressed during productive infection. Using computational methods, we carried out molecular modelling studies on the three-dimensional structures of the HCMV IL-10 proteins encoded by the transcripts detected in our work (cmvIL-10 (A), LAcmvIL-10 (B), E, F and H) and on their interaction with the human IL-10 receptor (IL-10R1). The modelling predicts clear differences between the isoform structures. Furthermore, the in silico simulations (molecular dynamics simulation and normal-mode analyses) allowed us to evaluate regions that contain potential receptor binding sites in each isoform. The analyses demonstrate that the complexes between the isoforms and IL-10R1 present different types of molecular interactions and consequently different affinities and stabilities. The knowledge about structure and expression of specific viral IL-10 isoforms has implications for understanding of their properties and role in HCMV immune evasion and pathogenesis.

In Silico and Structure-Based Assessment of Similar Variants Discovered in Tandem Repeats of BRCT Domains of BRCA1 and BARD1 To Characterize the Folding Pattern.

BRCA1 and BARD1 are important proteins in the homologous DNA damage repair pathways. Different genetic variants identified in these proteins have been clinically correlated with the occurrence of hereditary breast and ovarian cancer (HBOC). Variants of unknown significance (VUS) reported in the BRCT domains of BRCA1 and BARD1 substantiate the importance of BRCT domain-containing proteins for genomic integrity. To classify the pathogenicity of variants, in silico, structural and molecular dynamics (MD)-based approaches were explored. Different variants reported in the BRCT region were retrieved from cBioPortal, LOVD3, BRCA Exchange, and COSMIC databases to evaluate the pathogenicity. Multiple sequence alignment and superimposition of the structures of BRCA1 BRCT and BARD1 BRCT domains were performed to compare alterations in folding patterns. From 11 in silico predictions servers, variants reported to be pathogenic by 70% of the servers were considered for structural analysis. To our observations, four residue pairs of both the proteins were reported, harboring 11 variants, H1686Y, W1718L, P1749L, P1749S, and W1837L variants for BRCA1 BRCT and H606D, H606N, W635L, P657L, P657S, and W762F for BARD1 BRCT. MD simulations of the BRCT repeat regions of these variants and wild-type proteins were performed to evaluate the differences of folding patterns. Root mean square deviation (RMSD), R g, solvent-accessible surface area (SASA), and root mean square fluctuation (RMSF) of variants showed slight differences in the folding patterns from the wild-type proteins. Furthermore, principal components analysis of H1686Y, P1749S, and W1718L variants of BRCA1 showed less flexibility than the wild type, whereas that of H606D, W635L, and W762F of BARD1 showed more flexibility than the wild type. Normal mode analysis of the energy minima from the simulation trajectories revealed that most of the variants do not show much differences in the flexibility compared to the wild-type proteins, except for the discrete regions in the BRCT repeats, most prominently in the 1798-1801 amino acid region of BRCA1 and at the residue 744 in BARD1.

Identification of Torsional Modes in Complex Molecules Using Redundant Internal Coordinates: The Multistructural Method with Torsional Anharmonicity with a Coupled Torsional Potential and Delocalized Torsions.

Identification of internal-rotation modes in the normal-mode analysis of complex molecules is important for accurately describing the thermodynamic properties and kinetics of complex molecules when it is necessary to treat the anharmonicity of torsions and the multiconformer anharmonicity caused by the internal rotations. However, identifying and distinguishing torsional modes are very challenging because they are coupled to one another. In this work, we present a new strategy to automatically identify torsional vibrations and separate them from the other vibrational modes. By combining a redundant-internal-coordinate auto-generation procedure with torsional projection techniques, we automate the procedure of identifying and separating the coupled torsions, and we show that we can obtain robust and consistent results with various reasonable definitions of redundant-internal-coordinate sets. This model has been implemented in a new development version of the MSTor program to reduce the user input needed for multistructural and torsional anharmonicity (MS-T) calculations. The new method is called multistructural and torsional anharmonicity with a coupled torsional potential and delocalized torsions ([MS-T(CD)]. As example applications, we consider MS-T(CD) calculations on three molecules (2-hexyl radical, n-propylbenzene, and 5-hydroperoxy-6-oxohexanoylperoxy radical) that have multiple rotors and that provide challenges to choosing good sets of nonredundant-internal coordinates, and we compare the performance of the new strategy to five other torsion identification methods. The new strategy is demonstrated to be efficient in separating the torsional and nontorsional elements in the Hessian matrix, as well as in providing reasonable projected nontorsional frequencies to be used for calculations of partition function and thermochemistry.

A hybrid GNA instability

A semi-analytic admixed model formalism to study the stability effects of the inner crust regions against the local collective perturbations in non-rotating neutron stars is proposed. It consists of the viscoelastic heavy neutron-rich nuclei, superfluid neutrons, and degenerate quantum electrons. A normal spherical mode analysis yields a generalized linear dispersion relation multiparametrically mimicking the inner crust features of neutron stars. A hybrid gravito-nucleo-acoustic (GNA) instability mode is found to be excited. It is demonstrated that the electron density and the inner crust curvature act as its accelerating and antidispersive agents. In contrast, the heavy neutron-rich nucleus and neutron densities act as decelerating factors. The heavy nucleus density, electron density, and geometric curvature act as its destabilizers. It is only the neutron density that acts as the GNA stabilizing agent. The heavy neutron-rich nucleus and neutron densities are found to act as dispersive broadening factors to it. The high-K regions are the more unstable spectral windows indicating that the GNA mode plays a dominant role in the inner crust zone towards the local stability. Its fair reliability is indicated in light of the recent astronomic observed scenarios. It could be useful to explore acoustic mode signatures in non-rotating neutron stars and similar other compact astroobjects.

Negative inductor effects in nonlinear two-dimensional systems: Oscillatory neurons and memristors

Many chemical and physical systems show self-sustained oscillations that can be described by a set of nonlinear differential equations. The system enters oscillatory behavior by an intrinsic instability that leads to bifurcation. We analyze conducting systems that present oscillating response under application of external voltage or current. Phenomena like electrochemical corrosion and the spiking response of a biological neuron are well-known examples. These systems have applications in artificial neurons and synapses for neuromorphic computation. Their dynamical properties can be characterized by normal mode analysis of small expansion of the constituent nonlinear equations. The linearized model leads to the technique of ac frequency response impedance spectroscopy that can be obtained experimentally. We show a general description of two-variable systems formed by a combination of a fast variable (the voltage) and a slowing down internal variable, which produce a chemical inductor. A classification of bifurcations and stability is obtained in terms of the parameters of the intrinsic equivalent circuit including the case of a negative inductor. Thereafter, we describe a number of physical examples and establish the characterization of their properties: The electrocatalytic reaction with adsorbed intermediate species, an oscillating metal oxide memristor, and finally we discuss the signs of the equivalent circuit elements in the central model of neuroscience, the Hodgkin–Huxley model for an oscillating neuron.

Integrativesubtractive proteomics, immunoinformatics, docking, and simulation approaches reveal candidate vaccine against Sin Nombre orthohantavirus

The emergence of Sin Nombre orthohantavirus, an etiological agent of hantavirus cardiopulmonary syndrome, exacerbates the situation and imposes a heavy financial burden on healthcare organizations. Multidrug-resistant forms of the disease are prevalent, and there is currently no licensed commercial vaccine. Due to the numerous limitations of experimental vaccines, vaccines against various bacterial and viral diseases have developed via computational vaccine design. Several subtractive proteomics, immunoinformatics, docking, and simulation approaches were used in this study to develop a multi-epitope-based vaccine against Sin Nombre orthohantavirus. One possible antigenic protein-the glycoprotein precursor of surface glycoproteins (accession number >AAC42202.1)-was selected as a candidate for B cell-derived T cell epitopes mapping the detailed analysis of the core genome. Among the predicted epitopes, four epitopes (QVDWTKKSST, GLAASPPHL, SSYSYRRKLV, and MESGWSDTA), which were probably antigenic, nonallergenic, nontoxic, and water soluble, were used in the multi-epitope vaccine's construction. The shortlisted epitopes have the potency to cover 99.78% of the world's population, 97.93% of the Chinese population, and 97.36% of the Indian population. The epitopes were connected through AAY linkers and joined with >50S ribosomal adjuvant to enhance their efficacy. The vaccine comprises 182 amino acids with a molecular weight of 19.03770 kDa and an instability index of 26.52, indicating that the protein is stable. A molecular docking study revealed that the vaccine has a good binding affinity with TLR-4 and TLR-8, which is vital for inducing the immune system. Top-1 docked complexes of vaccine- TLR-4 and TLR-8 with the lowest binding energy of -12.52 kc/mol and -5.42 kc/mol, respectively, were considered for molecular dynamic simulation analysis. Furthermore, we predicted that the docked complexes are properly stable throughout simulation time in both normal mode and AMBER-based simulation analysis. The MMGBSA analysis calculated -122.17 and -125.4 net binding energies for the TLR-8- and TLR4-vaccine complexes, respectively, while the MMPBSA analysis estimated -115.63 and -118.19 for the TLR-8- and TLR4-vaccine complex, respectively, confirming that the binding stability with receptors is stable, which is important for inducing a strong response. However, the current work is computation-based, so experimental validation is highly recommended.

Engineering Modified mRNA-Based Vaccine against Dengue Virus Using Computational and Reverse Vaccinology Approaches.

Dengue virus belonging to the family Flaviviridae and its four serotypes are responsible for dengue infections, which extend over 60 countries in tropical and subtropical areas of the world including Pakistan. During the ongoing dengue outbreak in Pakistan (2022), over 30,000 cases have been reported, and over 70 lives have been lost. The only commercialized vaccine against DENV, Dengvaxia, cannot be administered as a prophylactic measure to cure this infection due to various complications. Using machine learning and reverse vaccinology approaches, this study was designed to develop a tetravalent modified nucleotide mRNA vaccine using NS1, prM, and EIII sequences of dengue virus from Pakistani isolates. Based on high antigenicity, non-allergenicity, and toxicity profiling, B-cell epitope, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) putative vaccine targets were predicted. Molecular docking confirmed favorable interactions between T-cell epitopes and their respective HLA alleles, while normal mode analysis validated high-affinity interactions of vaccine proteins with immune receptors. In silico immune simulations confirmed adequate immune responses to eliminate the antigen and generate memory. Codon optimization, physicochemical features, nucleotide modifications, and suitable vector availability further ensured better antigen expression and adaptive immune responses. We predict that this vaccine construct may prove to be a good vaccinal candidate against dengue virus in vitro as well.