Force Regime Research Articles

Pulling Forces Differentially Affect Refolding Pathways Due to Entangled Misfolded States in SARS-CoV-1 and SARS-CoV-2 Receptor Binding Domain

Single-molecule force spectroscopy (SMFS) experiments can monitor protein refolding by applying a small force of a few piconewtons (pN) and slowing down the folding process. Bell theory predicts that in the narrow force regime where refolding can occur, the folding time should increase exponentially with increased external force. In this work, using coarse-grained molecular dynamics simulations, we compared the refolding pathways of SARS-CoV-1 RBD and SARS-CoV-2 RBD (RBD refers to the receptor binding domain) starting from unfolded conformations with and without a force applied to the protein termini. For SARS-CoV-2 RBD, the number of trajectories that fold is significantly reduced with the application of a 5 pN force, indicating that, qualitatively consistent with Bell theory, refolding is slowed down when a pulling force is applied to the termini. In contrast, the refolding times of SARS-CoV-1 RBD do not change meaningfully when a force of 5 pN is applied. How this lack of a Bell response could arise at the molecular level is unknown. Analysis of the entanglement changes of the folded conformations revealed that in the case of SARS-CoV-1 RBD, an external force minimizes misfolding into kinetically trapped states, thereby promoting efficient folding and offsetting any potential slowdown due to the external force. These misfolded states contain non-native entanglements that do not exist in the native state of either SARS-CoV-1-RBD or SARS-CoV-2-RBD. These results indicate that non-Bell behavior can arise from this class of misfolding and, hence, may be a means of experimentally detecting these elusive, theoretically predicted states.

Investigation of the tradeoffs between tracking performance and energetics in heterogeneous variable recruitment fluidic artificial muscle bundles

In traditional hydraulic robotics, actuators must be sized for the highest possible load, resulting in significant energy losses when operating in lower force regimes. Variable recruitment fluidic artificial muscle (FAM) bundles offer a novel bio-inspired solution to this problem. Divided into individual MUs, each with its own control valve, a variable recruitment FAM bundle uses a switching control scheme to selectively bring MUs online according to load demand. To date, every dynamic variable recruitment study in the literature has considered homogeneous bundles containing MUs of equal size. However, natural mammalian muscle MUs are heterogeneous and primarily operate based on Henneman's size principle, which states that MUs are recruited from smallest to largest for a given task. Is it better for a FAM variable recruitment bundle to operate according to this principle, or are there other recruitment orders that result in better performance? What are the appropriate criteria for switching between recruitment states for these different recruitment orders? This paper seeks to answer these questions by performing two case studies exploring different bundle MU size distributions, analyzing the tradeoffs between tracking performance and energetics, and determining how these tradeoffs are affected by different MU recruitment order and recruitment state transition thresholds. The only difference between the two test cases is the overall force capacity (i.e. total size) of the bundle. For each test case, a Pareto frontier for different MU size distributions, recruitment orders, and recruitment state transition thresholds is constructed. The results show that there is a complex relationship between overall bundle size, MU size distributions, recruitment orders, and recruitment state transition thresholds corresponding to the best tradeoffs change along the Pareto frontier. Overall, these two case studies validate the use of Henneman's Size Principle as a variable recruitment strategy, but also demonstrate that it should not be the only variable recruitment method considered. They also motivate the need for a more complex variable recruitment scheme that dynamically changes the recruitment state transition threshold and recruitment order based on loading conditions and known system states, along with a co-design problem that optimizes total bundle size and MU size distribution.

Develop Tandem Tension Sensor to Gauge Integrin-Transmitted Molecular Forces.

DNA-based tension sensors have innovated the imaging and calibration of mechanosensitive receptor-transmitted molecular forces, such as integrin tensions. However, these sensors mainly serve as binary reporters, only indicating if molecular forces exceed one predefined threshold. Here, we have developed tandem tension sensor (TTS), which comprises two consecutive force-sensing units, each with unique force detection thresholds and distinct fluorescence spectra, thereby enabling the quantification of molecular forces with dual reference levels. With TTS, we revealed that vinculin is not required for transmitting integrin tensions at approximately 10 pN (piconewtons) but is essential for elevating integrin tensions beyond 20 pN in focal adhesions (FAs). Such high tensions have emerged during the early stage of FA formation. TTS also successfully detected changes in integrin tensions in response to disrupted actin formation, inhibited myosin activity, and tuned substrate elasticity. We also applied TTS to examine integrin tensions in platelets and revealed two force regimes, with integrin tensions surpassing 20 pN at cell central regions and 13-20 pN integrin tensions at the cell edge. Overall, TTS, especially the construct consisting of a hairpin DNA (13 pN opening force) and a shearing DNA (20 pN opening force), stands as a valuable tool for the quantification of receptor-transmitted molecular forces within living cells.

Propulsive performance of a heaving and pitching foil with large amplitudes in unsteady ground effect

To reveal the effect of ground on the force behavior, propulsion performance, and vortex dynamics of a flapping foil, we numerically study a flapping foil actuated by combined heaving and pitching motions with large amplitudes near a solid ground surface. The instantaneous forces in both streamwise and cross-stream directions undergo a sudden drop during upstroke in close ground effect. The time-averaged thrust is enhanced by the ground but varies non-monotonically with ground distance at high foil oscillating frequencies. Three force regimes are identified in lift production, giving rise to two equilibrium altitudes of zero lift, one stable and another unstable. Moreover, we propose a simple scaling law model by a path-length-based Strouhal number and ground effect for thrust and power performance of a large-amplitude flapping foil. The results of the model are consistent with numerical results and previous experimental studies. The vortex dynamics in the wake structure are largely affected by ground proximity; in particular, the formed vortex pairs and their orientations are sensitive to their initial relative positions. Different sources and mechanisms of satellite vortex formation are then discussed. The ground exerts little effect on the phase angles that optimize the propulsive efficiency. This study is expected to provide new insights into the development and maneuvering of flapping foil-based propulsive systems.

Flow film boiling on a sphere in the mixed and forced convection regimes

Saturated flow film boiling on a sphere has been numerically studied in this work for both vertical and horizontal flow configurations. The simulations were performed using a numerical methodology developed by the authors for boiling flows on three-dimensional unstructured meshes. For interface capturing, the coupled level set and volume of fluid method is used. The interface evolution, vapour wake dynamics and heat transfer have been thoroughly investigated by varying the saturated liquid flow velocity, sphere diameter and wall superheat. The relative importance of both the buoyancy and the inertial forces is described in terms of the Froude number $(Fr)$ . The vapour bubble evolves periodically at low $Fr$ values, while a stable vapour column develops at high $Fr$ values. The interface evolution pattern obtained in the present work is in good agreement with the results of experimental studies available in the literature. For all the values of $Fr$ , a stable vapour column develops for a large-diameter sphere and releases vapour bubbles of varying sizes. Furthermore, for a large-diameter sphere, surface capillary waves are observed at the interface, similar to the observations of some of the experimental studies available in the literature. The flow in the liquid and vapour wakes appears to be strongly coupled. The heat transfer in the present work is estimated using the spatially and temporally averaged Nusselt numbers. Finally, an fast Fourier transform analysis of the space-averaged Nusselt number reveals a strong interaction among the different forces.

Investigation of Laminar Forced and Mixed Convection in Horizontal Mini Tubes with Uniform Wall Heat Flux Boundary Condition

In this study, a numerical model is established to study the forced and mixed convection heat transfer in the laminar region for horizontal mini tube with different diameters (1.2 mm to 3.0 mm) under the uniform wall heat flux boundary condition. The Reynolds number is set from 100 to 2,000 and the uniform wall heat flux boundary condition is set at 10 and 20 kW/m2. The model is verified with well-established correlation to guarantee good accuracy. The existence of mixed convection is examined by (1) the ratio between the heat transfer coefficients at the top and the bottom of the tube, and (2) the temperature contour plot. Based on the simulation results, the existence of buoyancy superimposed on the main flow is strongly related to the tube diameter, the dimensionless location, the Reynolds number, and the heat flux applied. Under the same heating condition, for small diameter tube with insufficient length, buoyancy effect can never establish. The existing flow regime maps for macro tube were used to predict the forced and mixed convection regimes from the simulated mini tube results and discrepancy was found. A new flow regime map is hence developed for mini tubes, and it classified the simulation results with good accuracy.

Drag force regime in dry and immersed granular media.

The drag force acting on an intruder colliding with granular media is typically influenced by the impact velocity and the penetrating depth. In this paper, the investigation was extended to the dry and immersed scenarios through coupled simulations at different penetrating velocities. The drag force regime was clarified to exhibit velocity dependence in the initial contact stage, followed by the inertial transit stage with a F∼z^{2} (force-depth) relationship. Subsequently, it transitioned into the depth-dependent regime in both dry and immersed cases. The underlying rheological mechanism was explored, revealing that, in both dry and immersed scenarios, the granular bulk underwent a state relaxation process, as indicated by the granular inertial number. Additionally, the presence of the ambient fluid restricted the flow dynamics of the perturbed granular material, exhibiting a similar rheology as observed in the dry case.

Numerical analysis of a parallel triple-jet of liquid-sodium in a turbulent forced convection regime

In the present study, we have applied a combined wall-resolving dynamic Large-Eddy Simulation (LES) (for the velocity field) and Direct Numerical Simulation (DNS) (for the temperature field) approach for mixing of parallel triple-jets with different temperatures of liquid sodium in a turbulent forced convection regime. Because of the high thermal conductivity of sodium (a low-Prandtl fluid), we adopted the dynamic Smagorinsky subgrid closure for the unresolved velocity scales, while the thermal scales are fully resolved. Furthermore, the Time-dependent Reynolds-Averaged Navier-Stokes (T-RANS) approach with the high-Reynolds number variant (i.e. with the wall functions as boundary conditions along solid boundaries) of the four-equation eddy viscosity model (k−ε−kθ−εθ) was applied. The fine-mesh LES/DNS provided a close agreement with the experimental data for both velocity and temperature fields (for both first- and second-moments). In contrast, the coarse-mesh LES/DNS overestimated the turbulent kinetic energy profiles at different distances from the inlet plane. The T-RANS results confirmed a good agreement with the mean streamwise velocity and turbulent kinetic energy, as well as the mean temperature profiles. Finally, the analysis of power spectral density distributions of the temperature signal revealed that all simulation techniques captured a dominant flow frequency originating from the induced Kelvin-Helmholtz instabilities between the side and central jets. The presented combined dynamic LES/DNS approach is recommended for future simulations of the turbulent forced convection flows of low Prandtl fluids, especially if thermal fatigue effects need to be predicted correctly.

Convergence of ensemble forecast distributions in weak and strong forcing convective weather regimes

AbstractThe constraint of computational power and the huge number of degrees of freedom of the atmosphere means a sampling uncertainty exists in probabilistic ensemble forecasts. In our previous study, the uncertainty could be quantified, creating a convergence measure which converges proportional to in the limit of large ensemble size . This power law can then be extrapolated to determine how sampling uncertainty would decrease with larger ensemble sizes and hence find the necessary ensemble size. It is unknown, however, how the sampling uncertainty depends on different weather regimes. This study extends the previous idealised ensemble developed, by including weak and strong forcing convective weather regimes, to look at how sampling uncertainty convergence differs in each. Two ‐member ensembles were run, with weak and strong forcing respectively. Comparisons with a kilometre‐scale weather prediction model ensured realistic weak and strong forcing regimes by comparing the rain, convective available potential energy (CAPE), convective adjustment timescale, and distribution shapes throughout the diurnal cycle. Differences in distribution shape between the regimes led to differences in the convergence measure. Large differences in spread between weak and strong forcing runs throughout the hr period led to large differences in sampling uncertainty of the mean and standard deviation, which could be quantified according to well‐known equations. The timing of these differences was case‐dependent. For extreme statistics such as the quantile and for cases where there was precipitation, the moisture variables for the weak forcing case had the largest sampling uncertainty and required the most members for convergence proportional to . This was due to the tails of the weak forcing moisture variables containing the least amount of density. Different ensemble sizes will hence be required depending on whether one is in the weak or strong forcing convective weather regime.

Exploration of Stokes hydrodynamic law at molecular length scales.

The celebrated generalized Stokes law predicts that the velocity of a particle pulled through a liquid by an external force, Fex, is directly proportional to the force and inversely proportional to the friction ζ acted by the medium on the particle. We investigate the range of validity of the generalized Stokes law at molecular length scales by employing computer simulations to calculate friction by pulling a tagged particle with a constant force. We thus calculate friction for two model interaction potentials, Lennard-Jones and soft sphere, for several particle sizes, ranging from radius (a) smaller than the solvent particles to three times larger. We next obtain friction from diffusion (D) by using Einstein's relation between diffusion and friction ζ in an unperturbed liquid. We find a quantitative agreement between the two at a small-to-intermediate pulling force regime for all the sizes studied. The law does break down at a large pulling force beyond a threshold value. Importantly, the range of validity of Stokes' scheme to obtain friction increases substantially if we turn off the attractive part of the interaction potential. Additionally, we calculate the viscosity (η) of the unperturbed liquid and find a good agreement with the Stokes-Einstein relation ζ = Cηa for the viscosity dependence with a value of C close to 5 π, which is intermediate between the slip and stick boundary condition.

Influence of retardation and dispersive surfaces on the regimes of the lateral Casimir-Polder force

Influence of retardation and dispersive surfaces on the regimes of the lateral Casimir-Polder force

Flow‐ and scale‐dependent spatial predictability of convective precipitation combining different model uncertainty representations

AbstractConsidering a whole summer season in central Europe, we find that the operational, convection‐permitting ICON‐D2 ensemble prediction system is spatially underdispersive in convective precipitation forecasts. The spatial spread of hourly precipitation is insufficient to capture the inherent error adequately across all scales (up to 300 km) and forecast times (up to 24 h). This lack of spread becomes more pronounced in the weak convective forcing regime. Using physically based stochastic perturbations in the planetary boundary layer is beneficial and leads to a reduction in spatial error at scales larger than 20 km and increases the spread at scales less than 50 km during weak forcing of convection, whereas the effect is almost neutral during strong forcing. Complementing the stochastic perturbations by perturbed parameters in the microphysics scheme shows an additive effect on spatial error and spread for a characteristic case study. Assessing the practical predictability of convective precipitation in a flow‐dependent manner is crucial, and our approach of combining multiple sources of uncertainty proves beneficial in mitigating the spatial underdispersion across scales, particularly during weak convective forcing.

Sublinear drag regime at mesoscopic scales in viscoelastic materials.

Stressed soft materials commonly present viscoelastic signatures in the form of power-law or exponential decay. Although exponential responses are the most common, power-law time dependencies arise peculiarly in complex soft materials such as living cells. Understanding the microscale mechanisms that drive rheologic behaviors at the macroscale shall be transformative in fields such as material design and bioengineering. Using an elastic network model of macromolecules immersed in a viscous fluid, we numerically reproduce those characteristic viscoelastic relaxations and show how the microscopic interactions determine the rheologic response. The macromolecules, represented by particles in the network, interact with neighbors through a spring constant k and with fluid through a non-linear drag regime. The dissipative force is given by γvα, where v is the particle's velocity, and γ and α are mesoscopic parameters. Physically, the sublinear regime of the drag forces is related to micro-deformations of the macromolecules, while α ≥ 1 represents rigid cases. We obtain exponential or power-law relaxations or a transitional behavior between them by changing k, γ, and α. We find that exponential decays are indeed the most common behavior. However, power laws may arise when forces between the macromolecules and the fluid are sublinear. Our findings show that in materials not too soft not too elastic, the rheological responses are entirely controlled by α in the sublinear regime. More specifically, power-law responses arise for 0.3 ⪅ α ⪅ 0.45, while exponential responses for small and large values of α, namely, 0.0 ⪅ α ⪅ 0.2 and 0.55 ⪅ α ⪅ 1.0.

Emergence of slip-ideal-slip behavior in tip-links serve as force filters of sound in hearing

Tip-links in the inner ear convey force from sound and trigger mechanotransduction. Here, we present evidence that tip-links (collectively as heterotetrameric complexes of cadherins) function as force filters during mechanotransduction. Our force-clamp experiments reveal that the tip-link complexes show slip-ideal-slip bond dynamics. At low forces, the lifetime of the tip-link complex drops monotonically, indicating slip-bond dynamics. The ideal bond, rare in nature, is seen in an intermediate force regime where the survival of the complex remains constant over a wide range. At large forces, tip-links follow a slip bond and dissociate entirely to cut-off force transmission. In contrast, the individual tip-links (heterodimers) display slip-catch-slip bonds to the applied forces. While with a phenotypic mutant, we showed the importance of the slip-catch-slip bonds in uninterrupted hearing, our coarse-grained Langevin dynamics simulations demonstrated that the slip-ideal-slip bonds emerge as a collective feature from the slip-catch-slip bonds of individual tip-links.

Structurally different chemical chaperones show similar mechanical roles with independent molecular mechanisms.

Osmolytes are well known to protect the protein structure against different chemical and physical denaturants. Since their actions with protein surfaces are mechanistically complicated and context dependent, the underlying molecular mechanism is not fully understood. Here, we combined single-molecule magnetic tweezers and molecular dynamics (MD) simulation to explore the mechanical role of osmolytes from two different classes, trimethylamine N-oxide (TMAO) and trehalose, as mechanical stabilizers of protein structure. We observed that these osmolytes increase the protein L mechanical stability by decreasing unfolding kinetics while accelerating the refolding kinetics under force, eventually shifting the energy landscape toward the folded state. These osmolytes mechanically stabilize the protein L and plausibly guide them to more thermodynamically robust states. Finally, we observed that osmolyte-modulated protein folding increases mechanical work output up to twofold, allowing the protein to fold under a higher force regime and providing a significant implication for folding-induced structural stability in proteins.

The appearance of oscillatory flows within a horizontal packed bed partly heated from below

We report on a numerical investigation of the unsteady mixed convective flow in a channel through a horizontal porous layer under localised isothermal heating from below to probe the oscillatory flow and thermal characteristics. The study was carried out for water flow within a plane channel containing stainless steel spherical particles. For this study, the channel height/particle diameter ratio was H/d=100 and the porosity was ɛ=0.35. The effects of the imposed pressure-driven flow characterised by the Péclet number (0.1≤Pe≤1000), and heating represented by the Rayleigh number (105≤Ra≤2×107), are investigated. The results reveal that for low Péclet numbers, steady free convective flows are dominant, while for high Péclet numbers, steady forced convective flows dominate. Importantly, no oscillatory flows are found to develop in the free and forced convection regimes. However, for moderate Péclet numbers, oscillatory mixed convective flows occur with different periodic, quasi-periodic, and chaotic flow behaviours. In addition, for low Rayleigh numbers, Ra≤106, the Nusselt number is not influenced by the Péclet number for Pe≤1. Nevertheless, for high Rayleigh numbers, Ra≥2×106, it is observed that there always exists a critical Péclet number for which the Nusselt number is a minimum. The effects of the Péclet and Rayleigh numbers on the local and average temperature disparity between the fluid and solid phases are then investigated.

Solitary waves in electro-mechanical lattices

We introduce and study both analytically and numerically a class of microelectromechanical chains aiming to turn them into transmission lines of solitons. Mathematically, their analysis reduces to the study of a spatially one-dimensional nonlinear Klein–Gordon equation with a model dependent onsite nonlinearity induced by the electrical forces. Since the basic solitons appear to be unstable for most of the force regimes, we introduce a stabilizing algorithm and demonstrate that it enables a stable and persisting propagation of solitons. Among other fascinating nonlinear formations induced by the presented models, we mention the “meson”: a stable square shaped pulse with sharp fronts that expands with a sonic speed, and “flatons”: flat-top solitons of arbitrary width.

On the use of thermal forces to probe kinesin's response to force.

The stepping dynamics of cytoskeletal motor proteins determines the dynamics of cargo transport. In its native cellular environment, a molecular motor is subject to forces from several sources including thermal forces and forces ensuing from the interaction with other motors bound to the same cargo. Understanding how the individual motors respond to these forces can allow us to predict how they move their cargo when part of a team. Here, using simulation, we show that details of how the kinesin motor responds to small assisting forces-which, at the moment, are not experimentally constrained-can lead to significant changes in cargo dynamics. Using different models of the force-dependent detachment probability of the kinesin motor leads to different predictions on the run-length of the cargo they carry. These differences emerge from the thermal forces acting on the cargo and transmitted to the motor through the motor tail that tethers the motor head to the microtubule. We show that these differences appear for cargo carried by individual motors or motor teams, and use our findings to propose the use of thermal forces as a probe of kinesin's response to force in this otherwise inaccessible force regime.

Impacts of Permeability Heterogeneity and Background Flow on Supercritical CO2 Dissolution in the Deep Subsurface

AbstractMotivated by CO2 capture and sequestration (CCS) design considerations, we consider the coupled effects of permeability heterogeneity and background flow on the dissolution of a supercritical CO2 lens into an underlying deep, confined aquifer. We present the results of a large‐scale Monte Carlo simulation study examining the interaction of background flow rate and three parameters describing multi‐Gaussian log‐permeability fields: mean, variance, and correlation length. Hundreds of high‐resolution simulations were performed using the PFLOTRAN finite volume software to model CO2 dissolution in a kilometer‐scale aquifer over 1,000 years. Predictive dimensionless scaling relationships relating CO2 dissolution rate to heterogeneity statistics, Rayleigh (Ra) and Péclet (Pe) numbers were developed for both gravitationally dominated free convection to background flow‐dominated forced convection regimes. An empirical criterion, Pe = Ra3/4, was discovered for regime transition. All simulations converged quickly to a quasi‐steady, approximately linear dissolution rate. However, this rate displayed profound variability between permeability field realizations sharing the same heterogeneity statistics, even under mild permeability heterogeneity. In general, increased heterogeneity was associated with a lower mean and higher variance of dissolution rate, undesirable from a CCS design perspective. The relationship between dissolution rate and background flow was found to be complex and nonlinear. Dimensionless scaling relationships were uncovered for a number of special cases. Results call into question the validity of the Boussinesq approximation in the context of modest‐to‐high background flow rates and the general applicability of numerical simulations without background flow.

Evaluating the influence of cage motion on the growth and shell characteristics of oysters (Crassostrea virginica) among several gear types

An influx of new oyster culture gear provides growers with an expanded ability to grow oysters throughout the water column. Each gear type is exposed to a different regime of physical forces, which is thought to affect oyster production differently; however, there is a poor understanding of the physical conditions inside cages and how they influence the production rate and quality of oysters. A greater understanding of the fundamental relationships between cage motion, oyster growth, and shell shape could help to improve the efficiency of off-bottom oyster production. Such understanding is critical for tailoring gear selection and tuning gear performance to suit grower needs. To address this void, cage motion, internal oyster movement, and oyster growth among three common cultivation methods (Virginia-style bottom cages, Seapa® long-line baskets, and floating cages) were monitored over a single growing season to clarify the role of the physical environment on oyster performance (shell and tissue growth). The averages and variance in motion among each cultivation method were noticeably different, which resulted in significant differences in the growth rate and quality of oysters they produced. Movement of the floating cages and long-line baskets could largely be explained by wind waves generated from a single direction in the field (r2 = 0.49, r2 = 0.36, respectively), while bottom cage movement was far less affected by wind waves. The changes in physical conditions inside each cultivation method demonstrated a trade-off between shell growth rate (a metric of time to market) and shell and meat quality (representative of crop value). These results can help inform growers wishing to strategically adopt cultivation methods that are most aligned with their production goals.