Accurate Perturbation Research Articles

The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis.

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvβ6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvβ6.

Complex Multi-nonlinearity for piezoelectric energy harvesting systems based on an accurate higher-order perturbation method

A theoretical model of a complex nonlinear coupling energy harvester under hybrid excitations is established with analytical and numerical solutions. Different orders of the method of multiple scales are derived to approximate and analyze the equation of motion for the electromechanical coupling system, thus obtaining higher-order approximate analytical solutions for its operating status and output performance indicators. The significant effects of external excitation, linear and nonlinear damping coefficients, as well as impedance on the transverse displacement, voltage, and power of higher-order and lower-order methods are analyzed. The results show that higher-order solution methodology are more sensitive to parameter excitation. For a large damping, the higher-order analysis has more excellent performance in capturing energy. The higher order method shows more pronounced nonlinear softening phenomenon and it is more suitable for low frequency environments. The higher order methods improves solution accuracy of piezoelectric energy harvesting systems. Consequently, it is easier to derive the nonlinear performance of the harvesting systems, and thus improves the average output power.

Analytically separating the source of the Teukolsky equation

Recent gravitational wave detections from black hole mergers have underscored the critical role black hole perturbation theory and the Teukolsky equation play in understanding the behavior of black holes. The separable nature of the Teukolsky equation has long been leveraged to study the vacuum linear Teukolsky equation; however, as theory and measurements advance, solving the sourced Teukolsky equation is becoming a frontier of research. In particular, second-order calculations, such as in quasinormal mode and self-force problems, have extended sources. This paper presents a novel method for analytically separating the Teukolsky equation’s source, aimed to improve efficiency. Separating the source is a nontrivial problem due to the angular and radial mixing of generic quantities in Kerr spacetime. We provide a proof-of-concept demonstration of our method and show that it is accurate, separating the Teukolsky source produced by the stress-energy tensor of an ideal gas cloud surrounding a Kerr black hole. The detailed application of our method is provided in an accompanying notebook. Our approach opens up a new avenue for accurate black hole perturbation theory calculations with sources in both the time and frequency domain. Published by the American Physical Society 2024

Machine Learning K-Means Clustering in Interpolative Separable Density Fitting Algorithm: Advancing Accurate and Efficient Cubic-Scaling Density Functional Perturbation Theory Calculations within Plane Waves.

Density functional perturbation theory (DFPT) is a crucial tool for accurately describing lattice dynamics. The adaptively compressed polarizability (ACP) method reduces the computational complexity of DFPT calculations from O(N4) to O(N3) by combining the interpolative separable density fitting (ISDF) algorithm. However, the conventional QR factorization with column pivoting (QRCP) algorithm, used for selecting the interpolation points in ISDF, not only incurs a high cubic-scaling computational cost, O(N3), but also leads to suboptimal convergence. This convergence issue is particularly pronounced when considering the complex interplay between the external potential and atomic displacement in ACP-based DFPT calculations. Here, we present a machine learning K-means clustering algorithm to select the interpolation points in ISDF, which offers a more efficient quadratic-scaling O(N2) alternative to the computationally intensive cubic-scaling O(N3) QRCP algorithm. We implement this efficient K-means-based ISDF algorithm to accelerate plane-wave DFPT calculations in KSSOLV, which is a MATLAB toolbox for performing Kohn-Sham density functional theory calculations within plane waves. We demonstrate that this K-means algorithm not only offers comparable accuracy to QRCP in ISDF but also achieves better convergence for ACP-based DFPT calculations. In particular, K-means can remarkably reduce the computational cost of selecting the interpolation points by nearly 2 orders of magnitude compared to QRCP in ISDF.

Carrying Capacity of Low Earth Orbit Computed Using Source-Sink Models

The low-Earth-orbit (LEO) environment will likely experience an exponential growth of the anthropogenic space object population, also due to the many proposed large constellations, which could negatively affect the sustainability of the space environment if no proper regulatory actions are introduced. This paper introduces a methodology to analyze high-capacity sustainable solutions of the LEO region from 200 to 900 km altitude. Sustainability is assessed through the stable equilibrium points of a source-sink model called MIT Orbital Capacity Assessment Tool 3 (MOCAT-3). Capacity is estimated using an optimization procedure that aims to compute the optimal launch rate that maximizes the number of satellites in LEO, subject to a risk-rate constraint. Results show that the sustainable number of satellites increases with the risk rate constraint. Moreover, the resilience of the proposed solutions is tested against a more accurate time-varying atmospheric density model and perturbations of the initial equilibrium population. The compatibility of the proposed solutions with future traffic launches and a strategy to accommodate future traffic needs are presented. Limitations of the current work are discussed, chiefly the importance of validation of model coefficients and behavior before resulting capacity estimates are used to guide actual decision-making.

Electronic structure of Ta2O5 polymorphs: Variation trend of band gap and the role of oxygen vacancies

We provide a systematic study on the electronic structure of a series of Ta2O5 polymorphs using standard density functional theory (DFT) calculations as well as the more accurate many-body perturbation theory within the GW approximation. For the defect-free polymorphs, the variation trend of band gap can be microscopically related to the strength of orbital hybridization, and to the macroscopic bulk formation energy. The presence of oxygen vacancies is found to have profound effects on the electronic properties near the Fermi level, notably the reduction of band gap and gap closure (insulator-to-metal transition). Furthermore, depending on the vacancy sites, the band gap of some defective system may be enlarged with comparison to its defect-free counterpart. Such an anomalous behavior originates from the unexpected formation of Ta–Ta bonds.

Sliding mode control of electro-hydraulic servo system based on double observers

Abstract. In this paper, in order to solve the real-time state value acquisition and external-disturbance problems faced during the working process of an electro-hydraulic servo system, a sliding mode controller based on dual observers is designed, which enables the system to effectively acquire the state value and realize better control accuracy. The method uses a high-gain observer to obtain the system state in real time and then adds a perturbation observer to provide more accurate state and perturbation observations for the sliding mode controller. The dual observer observes the obtained states and external perturbations and feeds these back to the sliding mode controller to control the system accurately. Finally, the observation performance of the observers is verified by comparative simulation, and the proposed control method can improve the control accuracy.

Theoretical insights into the photophysics of an unnatural base Z: A MS-CASPT2 investigation.

We have employed the highly accurate multistate complete active space second-order perturbation theory (MS-CASPT2) method to investigate the photoinduced excited state relaxation properties of one unnatural base, namely Z. Upon excitation to the S2 state of Z, the internal conversion to the S1 state would be dominant. From the S1 state, two intersystem crossing paths leading to the T2 and T1 states and one internal conversion path to the S0 state are possible. However, considering the large barrier to access the S1 /S0 conical intersection and the strong spin-orbit coupling between S1 and T2 states (>40 cm-1 ), the intersystem crossing to the triplet manifolds is predicted to be more preferred. Arriving at the T2 state, the internal conversion to the T1 state and the intersystem crossing back to the S1 state are both possible considering the S1 /T2 /T1 three-state intersection near the T2 minimum. Upon arrival at the T1 state, the deactivation to S0 can be efficient after overcoming a small barrier to access T1 /S0 crossing point, where the spin-orbit coupling (SOC) is as large as 39.7 cm-1 . Our present work not only provides in-depth insights into the photoinduced process of unnatural base Z, but can also help the future design of novel unnatural bases with better photostability.

Seasonally varying outgassing as an explanation for dark comet accelerations

Significant nonradial, nongravitational accelerations with magnitudes incompatible with radiation-driven effects have been reported in seven photometrically inactive near-Earth objects. Two of these objects exhibit large transverse accelerations (i.e., within the orbital plane but orthogonal to the radial direction), and six exhibit significant out-of-plane accelerations. Here, we find that anisotropic outgassing resulting from differential heating on a nucleus with nonzero spin-pole obliquity, averaged over an eccentric orbit, can explain these accelerations for most of the objects. This balanced outgassing model depends on three parameters — the spin pole orientation (R.A. and Dec.) and an acceleration magnitude. For these “dark comets” (excepting 2003 RM), we obtain parameter values that reproduce the observed nongravitational accelerations. We derive formulae for the component accelerations under certain assumptions for the acceleration scaling over heliocentric distance. Although we lack estimates of these objects’ spin axes to confirm our values, this mechanism is nevertheless a plausible explanation for the observed accelerations, and produces accurate perturbations to the heliocentric motions of most of these objects. This model may also be applied to active objects outside of the dark comets group.

Improved perturbation solution for viscous flow in a dilating–contracting permeable channel with velocity slip

Recently, Mandal and Ghosh [“Lie-group method solutions for a viscous flow in a dilating-squeezing permeable channel with velocity slip,” Phys. Fluids 35, 047121 (2023)] constructed perturbation solutions for viscous flow in porous channels with a slip condition and moving walls restricted to slow wall dilation–contraction rates. Herein, we show that this “slowness” assumption may be completely removed. In doing so, we develop a more widely applicable and more accurate perturbation scheme for all dilation–contraction rates. Our strategy involves generating new and exact solutions to the linear, inviscid problem with slip condition, and then we draw on this precise form to construct more accurate perturbation expansions for solutions to the nonlinear flow model than are currently available.

Stacking up Electron-Rich and Electron-Deficient Monolayers to Achieve Extraordinary Mid- to Far-Infrared Excitonic Absorption: Interlayer Excitons in the C3B/C3N Bilayer

Our ability to efficiently detect and generate far-infrared (i.e., terahertz) radiation is vital in areas spanning from biomedical imaging to interstellar spectroscopy. Despite decades of intense research, bridging the terahertz gap between electronics and optics remains a major challenge due to the lack of robust materials that can efficiently operate in this frequency range, and two-dimensional (2D) type-II heterostructures may be ideal candidates to fill this gap. Herein, using highly accurate many-body perturbation theory within the GW plus Bethe-Salpeter equation approach, we predict that a type-II heterostructure consisting of an electron-rich ${\mathrm{C}}_{3}\mathrm{N}$ and an electron deficient ${\mathrm{C}}_{3}\mathrm{B}$ monolayers can give rise to extraordinary optical activities in the mid- to far-infrared range. ${\mathrm{C}}_{3}\mathrm{N}$ and ${\mathrm{C}}_{3}\mathrm{B}$ are two graphene-derived 2D materials that have attracted increasing research attention. Although both ${\mathrm{C}}_{3}\mathrm{N}$ and ${\mathrm{C}}_{3}\mathrm{B}$ monolayers are moderate-gap 2D materials, and they couple only through the rather weak van der Waals interactions, the bilayer heterostructure surprisingly supports extremely bright, low-energy interlayer excitons with large binding energies of 0.2--0.4 eV, offering an ideal material with interlayer excitonic states for mid- to far-infrared applications at room temperature. We also investigate in detail the properties and formation mechanism of the inter- and intralayer excitons.

An accurate zeroth-order perturbation theory for solving power-law potentials within the frame work of the asymptotic iteration method

An accurate zeroth-order perturbation theory for solving power-law potentials within the frame work of the asymptotic iteration method

Introduction to a Twin Dual-Axis Robotic Platform for Studies of Lower Limb Biomechanics.

This paper presents a twin dual-axis robotic platform system which is designed for the characterization of postural balance under various environmental conditions and quantification of bilateral ankle mechanics in 2 degrees-of-freedom (DOF) during standing and walking. Methods: Validation experiments were conducted to evaluate performance of the system: 1) to apply accurate position perturbations under different loading conditions; 2) to simulate a range of stiffness-defined mechanical environments; and 3) to reliably quantify the joint impedance of mechanical systems. In addition, several human experiments were performed to demonstrate the system's applicability for various lower limb biomechanics studies. The first two experiments quantified postural balance on a compliance-controlled surface (passive perturbations) and under oscillatory perturbations with various frequencies and amplitudes (active perturbations). The second two experiments quantified bilateral ankle mechanics, specifically, ankle impedance in 2-DOF during standing and walking. The validation experiments showed high accuracy of the platform system to apply position perturbations, simulate a range of mechanical environments, and quantify the joint impedance. Results of the human experiments further demonstrated that the platform system is sensitive enough to detect differences in postural balance control under challenging environmental conditions as well as bilateral differences in 2-DOF ankle mechanics. This robotic platform system will allow us to better understand lower limb biomechanics during functional tasks, while also providing invaluable knowledge for the design and control of many robotic systems including robotic exoskeletons, prostheses and robot-assisted balance training programs. Clinical and Translational Impact Statement- Our robotic platform system serves as a tool to better understand the biomechanics of both healthy and neurologically impaired individuals and to develop assistive robotics and rehabilitation training programs using this information.

High-performance lead-free quaternary antiperovskite photovoltaic candidate Ca6N2AsSb.

Accurate many-body perturbation theory-based calculations were used to study the electronic and excitonic properties of lead-free quaternary antiperovskite Ca6N2AsSb; large quasiparticle band gap renormalization, strong optical absorption, and low exciton binding energy, as well as high efficiency of >32% with a thickness of 500 nm were predicted.

A Cost Effective Scheme for the Highly Accurate Description of Intermolecular Binding in Large Complexes.

There has been a growing interest in quantitative predictions of the intermolecular binding energy of large complexes. One of the most important quantum chemical techniques capable of such predictions is the domain-based local pair natural orbital (DLPNO) scheme for the coupled cluster theory with singles, doubles, and iterative triples [CCSD(T)], whose results are extrapolated to the complete basis set (CBS) limit. Here, the DLPNO-based focal-point method is devised with the aim of obtaining CBS-extrapolated values that are very close to their canonical CCSD(T)/CBS counterparts, and thus may serve for routinely checking a performance of less expensive computational methods, for example, those based on the density-functional theory (DFT). The efficacy of this method is demonstrated for several sets of noncovalent complexes with varying amounts of the electrostatics, induction, and dispersion contributions to binding (as revealed by accurate DFT-based symmetry-adapted perturbation theory (SAPT) calculations). It is shown that when applied to dimeric models of poly(3-hydroxybutyrate) chains in its two polymorphic forms, the DLPNO-CCSD(T) and DFT-SAPT computational schemes agree to within about 2 kJ/mol of an absolute value of the interaction energy. These computational schemes thus should be useful for a reliable description of factors leading to the enthalpic stabilization of extended systems.

Interpreting denoising autoencoders with complex perturbation approach

The goal of this study is to interpret denoising autoencoders by quantifying the importance of input pixel features for image reconstruction. The importance of pixel features is evaluated using the attributions of the pixel features to the latent variables of a denoising autoencoder used for image reconstruction. Pixel attributions are computed using a highly accurate and automatable perturbation approach and are plotted as saliency maps. Saliency maps highlight the contribution of the pixels for image reconstruction. The proposed approach produces more meaningful and understandable explanations than guided backpropagation and layer wise propagation methods. Three sanity checks are introduced to verify the fidelity of the generated saliency maps and also to elucidate the influence of inputs on the latent variables. The classification accuracy of images is significantly lowered when the most important pixel regions highlighted by the saliency maps are corrupted validating the proposed approach.

Induced-Fit Docking Enables Accurate Free Energy Perturbation Calculations in Homology Models.

Homology models have been used for virtual screening and to understand the binding mode of a known active compound; however, rarely have the models been shown to be of sufficient accuracy, comparable to crystal structures, to support free-energy perturbation (FEP) calculations. We demonstrate here that the use of an advanced induced-fit docking methodology reliably enables predictive FEP calculations on congeneric series across homology models ≥30% sequence identity. Furthermore, we show that retrospective FEP calculations on a congeneric series of drug-like ligands are sufficient to discriminate between predicted binding modes. Results are presented for a total of 29 homology models for 14 protein targets, showing FEP results comparable to those obtained using experimentally determined crystal structures for 86% of homology models with template structure sequence identities ranging from 30 to 50%. Implications for the use and validation of homology models in drug discovery projects are discussed.

Many-core acceleration of the first-principles all-electron quantum perturbation calculations

The first-principles quantum perturbation theory, also called density-functional perturbation theory (DFPT), is the state-of-the-art formalism to directly link the experimental response properties of the materials with the quantum modeling of the electrons. Here in this work, we present an implementation of all-electron DFPT for massively parallel Sunway many-core architectures to accelerate DFPT calculation. We have paid special attention to the calculation of the response density matrix, the real-space integration of the response density as well as the response Hamiltonian matrix. We also employ the fast and massively parallel linear scaling scheme together with the load balance algorithm for the DFPT calculations to improve the scalability. Using the above approaches, the accurate first-principles quantum perturbation calculations can be extended over millions of cores.

Perturbation Solution for One-Dimensional Flow to a Constant-Pressure Boundary in a Stress-Sensitive Reservoir

Most analyses of fluid flow in porous media are conducted under the assumption that the permeability is constant. In some “stress-sensitive” rock formations, however, the variation of permeability with pore fluid pressure is sufficiently large that it needs to be accounted for in the analysis. Accounting for the variation of permeability with pore pressure renders the pressure diffusion equation nonlinear and not amenable to exact analytical solutions. In this paper, the regular perturbation approach is used to develop an approximate solution to the problem of flow to a linear constant-pressure boundary, in a formation whose permeability varies exponentially with pore pressure. The perturbation parameter αD is defined to be the natural logarithm of the ratio of the initial permeability to the permeability at the outflow boundary. The zeroth-order and first-order perturbation solutions are computed, from which the flux at the outflow boundary is found. An effective permeability is then determined such that, when inserted into the analytical solution for the mathematically linear problem, it yields a flux that is exact to at least first order in αD. When compared to numerical solutions of the problem, the result has 5% accuracy out to values of αD of about 2—a much larger range of accuracy than is usually achieved in similar problems. Finally, an explanation is given of why the change of variables proposed by Kikani and Pedrosa, which leads to highly accurate zeroth-order perturbation solutions in radial flow problems, does not yield an accurate result for one-dimensional flow.Article HighlightsApproximate solution for flow to a constant-pressure boundary in a porous medium whose permeability varies exponentially with pressure.The predicted flowrate is accurate to within 5% for a wide range of permeabilityvariations.If permeability at boundary is 30% less than initial permeability, flowrate will be 10% less than predicted by constant-permeability model.

Assessing the importance of nonlinearity for aircraft emissions' impact on O3 and PM2.5

In this study we utilize the Decoupled Direct Method (HDDM-3D) as implemented in the Community Multiscale Air Quality Model (CMAQ) to calculate first and second order sensitivity coefficients of O 3 and PM 2.5 concentrations with respect to aviation emissions during landing and takeoff (LTO) cycles at ten individual airports; five located in regions of attainment of O 3 and PM 2.5 NAAQS: Boston Logan (BOS), Kansas City (MCI), Raleigh-Durham (RDU), Seattle-Tacoma (SEA), and Tucson (TUS); and five airports in current nonattainment areas: Chicago O'Hare (ORD), Hartsfield- Jackson Atlanta (ATL), New York John F. Kennedy (JFK), Los Angeles (LAX), and Charlotte- Douglas (CLT). We utilize these coefficients in an attainment/nonattainment emission decrease/increase analysis to determine the importance of including second order sensitivity coefficients for quantifying O 3 and PM 2.5 concentration responses to LTO aircraft emission reductions near the airport. Sensitivity coefficients help to determine distinct chemical regimes, NO X -limited versus NO X -inhibited for the case of O 3 formation, and NH 3 -rich versus NH 3 -poor for the case of PM 2.5 formation. Overall, we find that NO X LTO emissions are the largest contributor to any potential nonlinearity in O 3 and PM 2.5 formation through LTO emissions. However, when utilizing Taylor series expansions to estimate O 3 and PM 2.5 concentration responses under LTO emission perturbation scenarios, differences in responses calculated using only first order coefficients and responses calculated using both first and second order coefficients were less than 1% for LTO emission perturbations less than 100%. Hence, we find from the results in this study that first order sensitivity coefficients are sufficient for constructing accurate LTO emissions perturbation scenarios. This study also demonstrates through the analyses performed, an illustration of how HDDM-based sensitivity calculations can be used to assess sector-specific impacts on attainment designations. • Sensitivities can help to determine distinct chemical regimes. • Aircraft NOx emissions contribute most to nonlinear chemistry. • Higher order sensitivities not needed for aircraft emission reduction strategies. • Novel approach to determine emissions sector contribution to attainment designations.