Born Model Research Articles

Including implicit solvation in the bond capacity polarization model.

We derive expressions corresponding to a coupling of the recently proposed Bond Capacity polarization model with implicit solvation by means of the generalized Born and conductor-like polarizable continuum models. The original bond capacity interaction kernel is in both cases augmented with a term that accounts for the reaction potential arising from the continuum. The expressions for energy gradients are derived within the recently introduced Lagrangian formalism for the efficient evaluation of energy gradients of nonvariational force fields.

Comparison between Born and Kirchhoff operators for least-squares reverse time migration and the constraint of the propagation of the background wavefield

The Born approximation and the Kirchhoff approximation are two frameworks that are extensively used in solving seismic migration/inversion problems. Both approximations assume a linear relationship between the primary reflected/scattered data to the corresponding physical model. However, different approximations result in different behaviors. For least-squares reverse time migration (LSRTM), most of the algorithms are constructed based on Born approximation. We have constructed a pair of Kirchhoff modeling and migration operators based on the Born modeling operator and the connection between the perturbation model and the reflectivity model, and then we compared the different performances between Born and Kirchhoff operators for LSRTM. Numerical examples on Marmousi model and SEAM 2D salt model indicate that LSRTM with Kirchhoff operators is a better alternative to that with Born operators for imaging complex structures. To reduce the computational cost, we also investigate a strategy by restricting the propagation of the background wavefield to a stopping time rather than the maximum recording time. And this stopping time can be chosen as half of the maximum recording time. This computational strategy can be used in LSRTM procedures of predicting the primary reflected data, calculating the step length, and computing the gradient. Theoretical analyses and numerical experiments are given to justify this computational strategy for LSRTM.

Synergistic long-range effects of mutations underlie aggregation propensities of amylin analogues.

The USFDA has approved pramlintide, commercially named Symlin (sIAPP), as adjunctive therapy for type 2 diabetes (T2D). This analogue of the human amylin peptide (hIAPP) has triple proline substitutions typical of the rat isoform (rIAPP). Recently, it was proposed that pramlintide solubility and aggregation resistance might be improved by incorporating further mutations, as S20R, screened from the wild-type porcine isoform (pIAPP), which leads to the variant named sIAPP+. To better elucidate how such properties might be systematically induced in rationally designed analogues, we performed comparative assessments of rIAPP, sIAPP, and sIAPP+ using replica-exchange molecular dynamics (REMD) with an accurate combination of force field Charmm22* and explicit aqueous solvation TIP4P/Ew. Our thermo-structural analyses show that sIAPP exhibits a thermal conversion channel of helices[Formula: see text]-sheets resembling hIAPP. This channel is depleted in rIAPP and is absent in sIAPP+. As a consequence, sIAPP+ presents an overall decrease of β-like secondary structures and an overstabilization of α-helices. Additionally, we observed in rIAPP and sIAPP+ an increase in the backbone RMSF of molecular terminals and the exposed area of key residues. These structural features of sIAPP+ suggest a nonamyloidogenic character, which is corroborated by our judicious estimate of the electrostatic component of the solvation free energy using a generalized Born model, and so it may constitute an alternative strategy to sIAPP as a peptide analogue of hIAPP. Furthermore, our findings confirm that different aggregation propensities of amylin and its analogues are synergistically modulated by long-range effects of key mutations. Graphical Abstract S20R-Pramlintide.

Selectivity of the KcsA potassium channel: Analysis and computation.

Ion channels regulate the flux of ions through cell membranes and play significant roles in many physiological functions. Most of the existing literature focuses on computational approaches based on molecular dynamics simulation or numerical solution of the modified Poisson-Nernst-Planck (PNP) system. In this paper, we present an analytical and computational study of a mathematical model of the KcsA potassium channel, including the effects of ion size (Bikerman model) and solvation energy (Born model). Under equilibrium conditions, we obtain an analytical solution of our modified PNP system, which is used to explain selectivity of KcsA of various ions (K^{+}, Na^{+}, Cl^{-}, Ca^{2+}, and Ba^{2+}) due to negative permanent charges inside the filter region and the effect of ion sizes. Our results show that K^{+} is always selected over Na^{+}, as smaller Na^{+} ions have larger solvation energy. As the amount of negative charges in the filter exceeds a critical value, divalent ions (Ca^{2+} and Ba^{2+}) can enter the filter region and block the KcsA channel. For the nonequilibrium cases, due to difficulties associated with a pure analytical or numerical approach, we use a hybrid analytical-numerical method to solve the modified PNP system. Our predictions of selectivity of KcsA channels and saturation phenomenon of the current-voltage (I-V) curve agree with experimental observations.

Nonlinear Elastic, Ultrasonic and Thermophysical Properties of Lead Telluride

We report the temperature-dependent elastic, thermal and ultrasonic properties of lead telluride (PbTe) along $$ \left $$ , $$ \left $$ , and $$ \left $$ orientations. The Born model is used to compute nonlinear second- and third-order elastic constants. Further, the higher order elastic constants have been used to compute ultrasonic velocities, ultrasonic Gruneisen parameters, thermal relaxation time, thermal conductivity, acoustic coupling constants, and ultrasonic attenuation. Additionally, some mechanical constants, e.g., Young’s modulus, bulk modulus, shear modulus, tetragonal modulus, Zener anisotropy factor, Breazeale nonlinear constants, and first-order pressure derivatives have been computed for PbTe. Born Criterion for mechanical stability is satisfied by PbTe, since the value of Pugh’s ratio (the ratio of bulk modulus and shear modulus) is less than 1.75 which shows brittle nature of PbTe. Computed results are correlated with theoretical and experimental data available in literatures.

Identifying potential GluN2B subunit containing N-Methyl-D-aspartate receptor inhibitors: an integrative in silico and molecular modeling approach

N-methyl-D-aspartate receptors (NMDARs), a class of ligand-gated ion channels, are involved in non-selective cation transport across the membrane. These are contained in glutamatergic synapse and produce excitatory effects leading to synaptic plasticity and memory function. GluN1-GluN2B, a subtype of NMDAR(s), has significant role in neurodegeneration, amyloid β (Aβ) induced synaptic dysfunction and loss. Thus, targeting and inhibiting GluN1-GluN2B may be effective in the management of neurodegenerative diseases including Alzheimer’s disease. In the present study, ligand and structure-based approaches were tried to identify the inhibitors. The pharmacophore, developed from co-crystallised ifenprodil, afforded virtual hits, which were further subjected through drug likeliness and PAINS filters to remove interfering compounds. Further comprehensive docking studies, free energy calculations and ADMET studies resulted in two virtual leads. The leads, ZINC257261614 and ZINC95977857 displayed good docking scores of −12.90 and −12.20 Kcal/mol and free binding energies of −60.83 and −61.83 Kcal/mol, respectively. The compounds were having acceptable predicted ADMET profiles and were subjected to molecular dynamic (MD) studies. The MD simulation produced stable complexes of these ligands with GluN1-GluN2B subunit having protein and ligand RMSD in acceptable limit.AbbreviationsADAlzheimer's diseaseADMEAbsorption distribution metabolism and excretionATDAmino terminal domainBBBBlood-brain barrierCNSCentral nervous systemCREBcAMP response element binding proteinCTDCarboxy-terminal domainGluGlutamateGMQEGlobal model quality estimationHTVSHigh throughput virtual screeningHIAHuman intestinal absorptionLGALamarckian genetic algorithmMDMolecular dynamicsMM-GBSAMolecular mechanics, the Generalised Born model for Solvent AccessibilityNMDARN-methyl-D-aspartate receptorsPAINSPan assay interference compoundsRMSDRoot-mean square deviationRMSFRoot-mean-square fluctuationSMARTSSMILES arbitrary target specificationSPstandard precisionXPextra precisionCommunicated by Ramaswamy H. Sarma

Elastic reflection waveform inversion with variable density

Elastic full-waveform inversion (FWI) provides a better description of the subsurface information than those given by the acoustic assumption. However, it suffers from a more serious cycle-skipping problem compared with the latter. Reflection waveform inversion (RWI) is able to build a good background model, which can serve as an initial model for elastic FWI. Because, in RWI, we use the model perturbation to explicitly fit reflections, such perturbations should include density, which mainly affects the dynamics. We applied Born modeling to generate synthetic reflection data using optimized perturbations of the P- and S-wave velocities and density. The inversion for the perturbations of the P- and S-wave velocities and density is similar to elastic least-squares reverse time migration. An incorrect background model will lead to misfits mainly at the far offsets, which can be used to update the background P- and S-wave velocities along the reflection wavepath. We optimize the perturbations and background models in an alternate way. We use two synthetic examples and a field-data case to demonstrate our proposed elastic RWI algorithm. The results indicate that our elastic RWI with variable density is able to build reasonably good background models for elastic FWI with the absence of low frequencies, and it can deal with the variable density, which is required in real cases.

Quasiperiodic Branches in the Thermoelectricity of Nanowires

Branches attached to a nanowire may significantly modify the transport of excitations along it due to wave interference. In this article, we study the thermoelectric properties of thin nanowires with quasiperiodically placed branches by means of a real-space renormalization plus convolution method developed for the Kubo–Greenwood formula, in which tight-binding and Born models are respectively used for the calculation of electrical and lattice thermal conductivities. The results show a substantial growth of the thermoelectric figure of merit (ZT) induced by the long-range quasiperiodic disorder, because it diminishes the thermal conduction of long wavelength acoustic phonons because such phonons are usually not altered by local defects nor by impurities. A remarkable reduction of the thermal conduction can be further achieved by using low sound velocity materials.

Generalized Born Implicit Solvent Models for Biomolecules.

It would often be useful in computer simulations to use an implicit description of solvation effects, instead of explicitly representing the individual solvent molecules. Continuum dielectric models often work well in describing the thermodynamic aspects of aqueous solvation and can be very efficient compared to the explicit treatment of the solvent. Here, we review a particular class of so-called fast implicit solvent models, generalized Born (GB) models, which are widely used for molecular dynamics (MD) simulations of proteins and nucleic acids. These approaches model hydration effects and provide solvent-dependent forces with efficiencies comparable to molecular-mechanics calculations on the solute alone; as such, they can be incorporated into MD or other conformational searching strategies in a straightforward manner. The foundations of the GB model are reviewed, followed by examples of newer, emerging models and examples of important applications. We discuss their strengths and weaknesses, both for fidelity to the underlying continuum model and for the ability to replace explicit consideration of solvent molecules in macromolecular simulations.

Influence of plasticizer nature on the analytical characteristics of ion-selective electrodes based on higher quaternary ammonium salts reversible to doubly charged inorganic anions

It has been established that membranes of carbonate and hydrogen phosphate selective electrodes based on higher quaternary ammonium salts are preferable to be plasticized with o-nitrophenyldecyl ether, membranes of sulfate, selenate, selenite-selective electrodes with 1-bromonaphthalene, sulfite, molybdate, tungstate-selective electrodes with dibutylphthalate. The use of an optimum plasticizer allows, in general, reducing both the lower detection limit of electrodes and the values of selectivity coefficients by about 1 order (depending on the interfering ion). A qualitative explanation is given to the results obtained from the Fouoss theory and the Born model.

Investigation of the probable homo-dimer model of the Xeroderma pigmentosum complementation group A (XPA) protein to represent the DNA-binding core

The Xeroderma pigmentosum complementation group A (XPA) protein functions as a primary damage verifier and as a scaffold protein in nucleotide excision repair (NER) in all higher organisms. New evidence of XPA’s existence as a dimer and the redefinition of its DNA-binding domain (DBD) raises new questions regarding the stability and functional position of XPA in NER. Here, we have investigated XPA’s dimeric status with respect to its previously defined DBD (XPA98-219) as well as with its redefined DBD (XPA98-239). We studied the stability of XPA98-210 and XPA98-239 homo-dimer systems using all-atom molecular dynamics simulation, and we have also characterized the protein–protein interactions (PPI) of these two homo-dimeric forms of XPA. After conducting the root mean square deviation (RMSD) analyses, it was observed that the XPA98-239 homo-dimer has better stability than XPA98-210. It was also found that XPA98-239 has a larger number of hydrogen bonds, salt bridges, and hydrophobic interactions than the XPA98-210 homo-dimer. We further found that Lys, Glu, Gln, Asn, and Arg residues shared the major contribution toward the intermolecular interactions in XPA homo-dimers. The binding free energy (BFE) analysis, which used the molecular mechanics Poisson–Boltzmann method (MM-PBSA) and the generalized Born and surface area continuum solvation model (GBSA) for both XPA homo-dimers, also substantiated the positive result in favor of the stability of the XPA98-239 homo-dimer.Communicated by Ramaswamy H. Sarma

The small organic molecule C19 binds and strengthens the KRAS4b-PDE\u03b4 complex and inhibits growth of colorectal cancer cells in vitro and in vivo

BackgroundColorectal cancer is the third most common cancer worldwide; and in 40% of all cases, KRAS4b-activating mutations occur. KRAS4b is transported by phosphodiesterase-6δ (PDEδ) to the plasma membrane, where it gets activated. PDEδ downregulation prevents redistribution and activation of KRAS4b. Thus, targeting the KRAS4b-PDEδ complex is a treatment strategy for colorectal cancer.MethodsUsing docking and molecular dynamics simulations coupled to molecular mechanics, the generalized born model and solvent accessibility (MMGBSA) approach to explore protein-ligand stability, we found that the compound ((2S)-N-(2,5-diclorofenil)-2-[(3,4-dimetoxifenil)metilamino]-propanamida), termed C19, bound and stabilized the KRAS4b-PDEδ complex. We investigated whether C19 decreases the viability and proliferation of colorectal cancer cells, in addition to knowing the type of cell death that it causes and if C19 decreases the activation of KRAS4b and their effectors.ResultsC19 showed high cytotoxicity in the colorectal cancer cell lines HCT116 and LoVo, with a stronger effect in KRAS-dependent LoVo cells. Importantly, C19 significantly decreased tumor size in a xenograft mouse model and showed lower side effects than 5-fluorouracil that is currently used as colorectal cancer treatment.ConclusionsMechanistically, the cytotoxic effect was due to increased apoptosis of tumor cells and decreased phosphorylation of Erk and Akt. Therefore, our results suggest that C19 may serve as a promising new treatment for colorectal cancer.

Coupling direct inversion to common-shot image-domain velocity analysis

Migration velocity analysis is a technique used to estimate the large-scale structure of the subsurface velocity model controlling the kinematics of wave propagation. For more stable results, recent studies have proposed to replace migration, adjoint of Born modeling, by the direct inverse of the modeling operator in the context of extended subsurface-offset domain. Following the same strategy, we have developed a two-way-wave-equation-based inversion velocity analysis (IVA) approach for the original surface-oriented shot gathers. We use the differential semblance optimization (DSO) objective function to evaluate the quality of inverted images depending on shot positions and to derive the associated gradient, an essential element to update the macromodel. We evaluate the advantages and limitations through applications of 2D synthetic data sets, first on simple models with a single-reflector embedded in various background velocities and then on the Marmousi model. The direct inverse attenuates migration smiles by compensating for geometric spreading and uneven illuminations. We slightly modified the original DSO objective function to remove spurious oscillations around interface positions in the velocity gradient. These oscillations are related to the fact that the locations of events in the image domain depend on the macromodel. We pay attention to the presence of triplicated wavefields. It appears that IVA is robust even if artifacts are observed in the seismic migrated section. The velocity gradient leads to a stable update, especially after a Gaussian smoothing over a wavelength distance. Coupling common-shot direct inversion to velocity analysis offers new possibilities for the extension to 3D in the future.

Targeting Outer Membrane Protein Component AdeC for the Discovery of Efflux Pump Inhibitor against AdeABC Efflux Pump of Multidrug Resistant Acinetobacter baumannii.

The structure and functioning of multidrug efflux systems provide us with a better understanding of the transport of various antibiotics, thus giving a path for the discovery of effective compounds for combating the multidrug resistance in Acinetobacter baumannii. In the present study, a number of computational techniques have been used to search for an inhibitor for the RND efflux pump, AdeABC, of A. baumannii targeting specifically its outermost component, i.e., AdeC. We have prepared the three-dimensional structure for AdeC using MODELLER v9.16 and identified its active binding site using SiteMap. Using high-throughput virtual screening, we identified compounds from a large library of biogenic compounds on the basis of their effective interaction at the binding site of AdeC. The validation of docking step was performed by plotting ROC curve (enrichment calculations). The docked complexes were further analyzed for their binding free energies by molecular mechanics using Generalized Born model and Solvent Accessibility (MMGBSA). The molecular dynamics simulation was performed for AdeC-ZINC77257599 complex using GROMACS. The present rational drug designing, molecular mechanics and molecular dynamics data provided an inhibitor, i.e, ZINC77257599 [(3R,4Z,6E,8E)-3-hydroxy-2,2,4-trimethyl-10-oxazol-5-yl-deca-4,6,8-trienamide], for the outer membrane protein component (AdeC) of efflux pump AdeABC of A. baumannii.

Explicit ions/implicit water generalized Born model for nucleic acids.

The ion atmosphere around highly charged nucleic acid molecules plays a significant role in their dynamics, structure, and interactions. Here we utilized the implicit solvent framework to develop a model for the explicit treatment of ions interacting with nucleic acid molecules. The proposed explicit ions/implicit water model is based on a significantly modified generalized Born (GB) model and utilizes a non-standard approach to define the solute/solvent dielectric boundary. Specifically, the model includes modifications to the GB interaction terms for the case of multiple interacting solutes-disconnected dielectric boundary around the solute-ion or ion-ion pairs. A fully analytical description of all energy components for charge-charge interactions is provided. The effectiveness of the approach is demonstrated by calculating the potential of mean force for Na+-Cl- ion pair and by carrying out a set of Monte Carlo (MC) simulations of mono- and trivalent ions interacting with DNA and RNA duplexes. The monovalent (Na+) and trivalent (CoHex3+) counterion distributions predicted by the model are in close quantitative agreement with all-atom explicit water molecular dynamics simulations used as reference. Expressed in the units of energy, the maximum deviations of local ion concentrations from the reference are within k B T. The proposed explicit ions/implicit water GB model is able to resolve subtle features and differences of CoHex distributions around DNA and RNA duplexes. These features include preferential CoHex binding inside the major groove of the RNA duplex, in contrast to CoHex biding at the "external" surface of the sugar-phosphate backbone of the DNA duplex; these differences in the counterion binding patters were earlier shown to be responsible for the observed drastic differences in condensation propensities between short DNA and RNA duplexes. MC simulations of CoHex ions interacting with the homopolymeric poly(dA·dT) DNA duplex with modified (de-methylated) and native thymine bases are used to explore the physics behind CoHex-thymine interactions. The simulations suggest that the ion desolvation penalty due to proximity to the low dielectric volume of the methyl group can contribute significantly to CoHex-thymine interactions. Compared to the steric repulsion between the ion and the methyl group, the desolvation penalty interaction has a longer range and may be important to consider in the context of methylation effects on DNA condensation.

Forbidden Resonant Raman Scattering in GaAs/AlAs Superlattices: Experiment and Calculations

The Raman spectra of GaAs/AlAs(100) superlattices are calculated and studied experimentally for various wave-vector directions. The experiments are performed when applying a confocal optical microscope combined with a micro-Raman spectrometer for various scattering geometries both for phonons with a wave vector directed along the normal to a superlattice and in the in-plane geometry. The frequencies and eigenvectors of phonons are calculated in the extended Born model approximation taking into account Coulomb interaction in the rigid-ion approximation. The Raman spectra are calculated in the scope of the deformation- potential mechanism; herewith, it turns out that additional peaks, which are not described in the scope of this approach, appear in the experimental spectra. It seems likely that these peaks appear due to the manifestation of Raman scattering forbidden by selection rules under resonance conditions. An attempt is made to explain the appearance of these peaks in the experimental spectra within the scope of inelastic phonon scattering at bound charges (phonons with a large dipole moment).

Untangling the nonlinearity in inverse scattering with data-driven reduced order models

The motivation of this work is an inverse problem for the acoustic wave equation, where an array of sensors probes an unknown medium with pulses and measures the scattered waves. The goal of the inversion is to determine from these measurements the structure of the scattering medium, modeled by a spatially varying acoustic impedance function. Many inversion algorithms assume that the mapping from the unknown impedance to the scattered waves is approximately linear. The linearization, known as the Born approximation, is not accurate in strongly scattering media, where the waves undergo multiple reflections before they reach the sensors in the array. Thus, the reconstructions of the impedance have numerous artifacts. The main result of the paper is a novel, linear-algebraic algorithm that uses a reduced order model (ROM) to map the data to those corresponding to the single scattering (Born) model. The ROM construction is based only on the measurements at the sensors in the array. The ROM is a proxy for the wave propagator operator, that propagates the wave in the unknown medium over the duration of the time sampling interval. The output of the algorithm can be input into any off-the-shelf inversion software that incorporates state of the art linear inversion algorithms to reconstruct the unknown acoustic impedance.

Resonant thermoelectric transport in atomic chains with Fano defects

Abstract

Absolute proton hydration free energy, surface potential of water, and redox potential of the hydrogen electrode from first principles: QM/MM MD free-energy simulations of sodium and potassium hydration.

The absolute intrinsic hydration free energy GH+,wat◦ of the proton, the surface electric potential jump χwat◦ upon entering bulk water, and the absolute redox potential VH+,wat◦ of the reference hydrogen electrode are cornerstone quantities for formulating single-ion thermodynamics on absolute scales. They can be easily calculated from each other but remain fundamentally elusive, i.e., they cannot be determined experimentally without invoking some extra-thermodynamic assumption (ETA). The Born model provides a natural framework to formulate such an assumption (Born ETA), as it automatically factors out the contribution of crossing the water surface from the hydration free energy. However, this model describes the short-range solvation inaccurately and relies on the choice of arbitrary ion-size parameters. In the present study, both shortcomings are alleviated by performing first-principle calculations of the hydration free energies of the sodium (Na+) and potassium (K+) ions. The calculations rely on thermodynamic integration based on quantum-mechanical molecular-mechanical (QM/MM) molecular dynamics (MD) simulations involving the ion and 2000 water molecules. The ion and its first hydration shell are described using a correlated ab initio method, namely resolution-of-identity second-order Møller-Plesset perturbation (RIMP2). The next hydration shells are described using the extended simple point charge water model (SPC/E). The hydration free energy is first calculated at the MM level and subsequently increased by a quantization term accounting for the transformation to a QM/MM description. It is also corrected for finite-size, approximate-electrostatics, and potential-summation errors, as well as standard-state definition. These computationally intensive simulations provide accurate first-principle estimates for GH+,wat◦, χwat◦, and VH+,wat◦, reported with statistical errors based on a confidence interval of 99%. The values obtained from the independent Na+ and K+ simulations are in excellent agreement. In particular, the difference between the two hydration free energies, which is not an elusive quantity, is 73.9 ± 5.4 kJ mol-1 (K+ minus Na+), to be compared with the experimental value of 71.7 ± 2.8 kJ mol-1. The calculated values of GH+,wat◦, χwat◦, and VH+,wat◦ (-1096.7 ± 6.1 kJ mol-1, 0.10 ± 0.10 V, and 4.32 ± 0.06 V, respectively, averaging over the two ions) are also in remarkable agreement with the values recommended by Reif and Hünenberger based on a thorough analysis of the experimental literature (-1100 ± 5 kJ mol-1, 0.13 ± 0.10 V, and 4.28 ± 0.13 V, respectively). The QM/MM MD simulations are also shown to provide an accurate description of the hydration structure, dynamics, and energetics.

The Debye-Hückel theory and its importance in modeling electrolyte solutions

A colleague at the Technical University of Denmark has often stated: “Life is too short for electrolytes”. Another well-known scientist in the field of molecular simulation has recently said during an international Thermodynamics conference: “All my life I have tried to keep myself away from water and electrolytes”. Sadly, what these statements correctly imply is that there are far too many unclear questions and concepts in electrolyte thermodynamics, and associated difficulties in modeling electrolyte solutions. In this work, we attempt to shed some light on some important concepts and misconceptions in electrolyte thermodynamics associated with the development of electrolyte equations of state, with emphasis on those based on the Debye-Hückel theory. Detailed mathematics is needed for some of the derivations but for brevity and in order to emphasize the principles rather than the derivations, the latter are omitted. We first discuss the peculiarities of electrolyte thermodynamics and associated modeling and continue with a literature review of equations of state for electrolyte solutions. Next we will provide a modern derivation of the Debye-Hückel and Born equations and discuss their assumptions in detail to answer some of the confusion that exists in current literature on the applicability ranges and show how the different versions of the Debye-Hückel and Born models are related. A discussion and outlook section conclude this review. Several of the statements in this work challenge “accepted beliefs” in electrolyte thermodynamics and, while we believe that this challenge is justified, we hope that a useful debate can result in improved and predictive thermodynamic models for electrolyte solutions.