Visualizing conformational space of functional biomolecular complexes by deep manifold learning

The cellular functions are executed by biological macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving conformational continuum of important biomolecular complexes at atomic level is essential to understand their functional mechanisms and to guide structure-based drug discovery. Here we introduce a deep learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy reconstructions of conformational continuum. AlphaCryo4D integrates 3D deep residual learning with manifold embedding of energy landscapes, which directs 3D clustering of markedly improved accuracy via an energy-based particle-voting algorithm. By applications of this approach to analyze five experimental datasets, we examine its generality in breaking resolution limit of visualizing dynamic components of functional complexes, in discovering 'invisible' lowly populated intermediates and in exploring their hidden conformational space. Our approach expands the realm of structural ensemble determination to the nonequilibrium regime at atomic level, thus potentially transforming biomedical research and therapeutic development.

Ultrafast nonequilibrium dynamic process of separate electron and hole during exciton formation in few-layer tungsten disulfide

Femtosecond transient absorption spectroscopy has been employed to unravel separate initial nonequilibrium dynamic process of photo-injected electrons and holes during the formation process of the lowest excitons at the K-valley...

Quantifying the flux as the driving force for nonequilibrium dynamics and thermodynamics in non-Michaelis–Menten enzyme kinetics

The driving force for active physical and biological systems is determined by both the underlying landscape and nonequilibrium curl flux. While landscape can be experimentally quantified from the histograms of the collected real-time trajectories of the observables, quantifying the experimental flux remains challenging. In this work, we studied the single-molecule enzyme dynamics of horseradish peroxidase with dihydrorhodamine 123 and hydrogen peroxide (H2O2) as substrates. Surprisingly, significant deviations in the kinetics from the conventional Michaelis–Menten reaction rate were observed. Instead of a linear relationship between the inverse of the enzyme kinetic rate and the inverse of substrate concentration, a nonlinear relationship between the two emerged. We identified nonequilibrium flux as the origin of such non-Michaelis–Menten enzyme rate behavior. Furthermore, we quantified the nonequilibrium flux from experimentally obtained fluorescence correlation spectroscopy data and showed this flux to led to the deviations from the Michaelis–Menten kinetics. We also identified and quantified the nonequilibrium thermodynamic driving forces as the chemical potential and entropy production for such non-Michaelis–Menten kinetics. Moreover, through isothermal titration calorimetry measurements, we identified and quantified the origin of both nonequilibrium dynamic and thermodynamic driving forces as the heat absorbed (energy input) into the enzyme reaction system. Furthermore, we showed that the nonequilibrium driving forces led to time irreversibility through the difference between the forward and backward directions in time and high-order correlations were associated with the deviations from Michaelis–Menten kinetics. This study provided a general framework for experimentally quantifying the dynamic and thermodynamic driving forces for nonequilibrium systems.

PHYSICAL AND CHEMICAL FEATURES OF DYNAMIC OF POLYMERIC FLUID

In order to determine the nature of processes of the dynamic polymer flow with simple chemical reactions in two-dimensional cylindrical geometry, objects — a sugar melt and a high molecular weight fraction of glutenin of flour — were chosen in the hydrodynamic description, which were investigated on a rotational rheometer HAAKE RotoVisco 1 and the Moisture Analyzer OHAUS MB23. The nonlinear dynamics of a viscous flow of a compressible, homogeneous liquid with chemical reactions is considered. A nonstationary exact solution of the Poiseuille type is obtained. This solution is used to investigate the effect of viscosity and chemical reactions of the first order on the characteristics of the nonequilibrium dynamic states of the system. The present results of the joint research of the specialists of the All-Union Research Institute of the Confectionery Industry and the MEPhI are a continuation of the work on the formation of structures in food disperse systems and indicate that similar features can also be manifested in real flows of polymer liquids in various industrial installations.

Multiscale Analysis of Time Irreversibility Based on Phase-Space Reconstruction and Horizontal Visibility Graph Approach

Time irreversibility is an important property of nonequilibrium dynamic systems. A visibility graph approach was recently proposed, and this approach is generally effective to measure time irreversibility of time series. However, its result may be unreliable when dealing with high-dimensional systems. In this work, we consider the joint concept of time irreversibility and adopt the phase-space reconstruction technique to improve this visibility graph approach. Compared with the previous approach, the improved approach gives a more accurate estimate for the irreversibility of time series, and is more effective to distinguish irreversible and reversible stochastic processes. We also use this approach to extract the multiscale irreversibility to account for the multiple inherent dynamics of time series. Finally, we apply the approach to detect the multiscale irreversibility of financial time series, and succeed to distinguish the time of financial crisis and the plateau. In addition, Asian stock indexes away from other indexes are clearly visible in higher time scales. Simulations and real data support the effectiveness of the improved approach when detecting time irreversibility.

O PROGRAMA DE PESQUISA DA ECOLOGIA HISTÓRICA

Resumo: Ecologia histórica é um novo programa de pesquisa interdisciplinar relacionado à compreensão das dimensões temporal e espacial nas relações das sociedades humanas com o seu ambiente local e os efeitos globais cumulativos dessas relações. Ecologia histórica contém postulados centrais que se referem a tipos qualitativos de alterações humano-mediadas dos ambientes naturais e seus efeitos na diversidade das espécies, entre outros parâmetros. Um termo central usado em ecologia histórica para situar comportamento humano e agência no ambiente é a paisagem, como derivado da geografia histórica, e não ao contrário de ecossistema, o qual provém de sistemas ecológicos. Ecologia histórica é similar à teoria dinâmica de não-equilíbrio, no entanto difere, no seu postulado, de alteração humano-mediada como um princípio de transformação da paisagem. Tais alterações, contra intuitivamente, podem envolver sucessão antropogênica primária e secundária que resultam em incremento líquido de diversidade alfa e beta. Ecologia histórica aplicada pode suprir as condições referenciais de profundidade temporal e conhecimento tradicional para restaurar paisagens pretéritas.Abstract:Historical ecology is a new interdisciplinary research program concerned with comprehending temporal and spatial dimensions in the relationships of human societies to local environments and the cumulative global effects of these relationships. Historical ecology contains core postulates that concern qualitative types of humanmediateddisturbanceofnaturalenvironmentsandtheeffectofthese on species diversity, among other parameters. A central term used in historical ecology to situate human behavior and agency in the environment is the landscape, as derived from historical geography, instead of the ecosystem, which is from systems ecology. Historical ecology is similar to nonequilibrium dynamic theory, but differs in its postulate of human-mediated disturbance as a principle of landscape transformation. Such disturbances counterintuitively may involve anthropogenic primary and secondary succession that result in net increases of alpha and even beta diversity. Applied historical ecology can supply the reference conditions of time depth and traditional knowledge to restore past landscapes.

Dynamic Adjustment of the Ocean Circulation to Self-Attraction and Loading Effects

The oceanic response to surface loading, such as that related to atmospheric pressure, freshwater exchange, and changes in the gravity field, is essential to our understanding of sea level variability. In particular, so-called self-attraction and loading (SAL) effects caused by the redistribution of mass within the land–atmosphere–ocean system can have a measurable impact on sea level. In this study, the nature of SAL-induced variability in sea level is examined in terms of its equilibrium (static) and nonequilibrium (dynamic) components, using a general circulation model that implicitly includes the physics of SAL. The additional SAL forcing is derived by decomposing ocean mass anomalies into spherical harmonics and then applying Love numbers to infer associated crustal displacements and gravitational shifts. This implementation of SAL physics incurs only a relatively small computational cost. Effects of SAL on sea level amount to about 10% of the applied surface loading on average but depend strongly on location. The dynamic component exhibits large-scale basinwide patterns, with considerable contributions from subweekly time scales. Departures from equilibrium decrease toward longer time scales but are not totally negligible in many places. Ocean modeling studies should benefit from using a dynamical implementation of SAL as used here.