Molecular Machinery Research Articles

Information Arbitrage in Bipartite Heat Engines

Heat engines and information engines have each historically served as motivating examples for the development of thermodynamics. While these two types of systems are typically thought of as two separate kinds of machines, recent empirical studies of specific systems have hinted at possible connections between the two. Inspired by molecular machines in the cellular environment, which in many cases have separate components in contact with distinct sources of fluctuations, we study bipartite heat engines. We show that a bipartite heat engine can produce net output work only by acting as an information engine. Conversely, information engines can extract more work than the work consumed to power them only if they have access to different sources of fluctuations, i.e., act as heat engines. We illustrate these findings first through an analogy to economics and a cyclically controlled 2D ideal gas. We then explore two analytically tractable model systems in more detail: a Brownian-gyrator heat engine, which we show can be reinterpreted as a feedback-cooling information engine, and a quantum-dot information engine, which can be reinterpreted as a thermoelectric heat engine. Our results suggest design principles for both heat engines and information engines at the nanoscale and ultimately imply constraints on how free-energy transduction is carried out in biological molecular machines. Published by the American Physical Society 2024

Molecular characterization, immunocorrelation analysis, WGCNA analysis and machine learning modeling of genes associated with copper death subtypes of laryngeal cancer.

Laryngeal cancer is a malignant tumor that originates from the mucous membrane of the larynx. Currently, the specific involvement mechanism of copper death in laryngeal cancer patients has not been deeply studied. This study aims to explore the molecular characteristics and clinical survival significance of copper death-related genes in laryngeal cancer. Relevant transcriptomes and clinical data were retrieved and downloaded from the GEO database. Differential expression genes related to laryngeal cancer and copper death were selected, and the immune function, clinical risk correlation, and survival prognosis were analyzed. The differential analysis results showed that the differential expression genes related to laryngeal cancer and Cu-proptosis included SLC31A1 and ATP7B, and there was interaction between the immune cell groups in the differential genes of copper death in laryngeal cancer. Decreasing the expression of the gene ANXA5 or increasing the expression of the gene SERPINH1 can increase the susceptibility to laryngeal cancer. Copper death-related genes can affect the survival prognosis of laryngeal cancer patients. Detection of changes in their expression can provide new diagnostic and treatment directions for the progression of early-stage laryngeal cancer.

Rotaxanes with a photoresponsive macrocycle modulate the lipid bilayers of large and giant unilamellar vesicles

Rotaxanes equipped with actuators hold great potential for developing highly functional molecular machines. Such systems could significantly enhance our ability to study and manipulate biological and artificial membranes. Here, we introduce a rotaxane with a ring featuring two azobenzene photoswitches, which retain their photoreversibility and can be stochastically shuttled along the axle in solution. Studies in model bilayers, supported by molecular dynamics simulations, show how azobenzene photoswitching alters the interaction of rotaxanes with surrounding lipids, leading to changes in lipid packing. Such changes in the lipid bilayer were leveraged to induce the light-triggered release of sulforhodamine B from large unilamellar vesicles. Additionally, light activation of the rotaxanes is shown to induce reversible contraction and expansion of giant unilamellar vesicles. The results provide novel insights into the interactions and operation of rotaxanes in lipid bilayers and their impact on membrane properties. This will aid in developing systems for precise membrane manipulation for applications in biomedicine and bioengineering.

Mechanistic and Therapeutic Implications of Protein and Lipid Sialylation in Human Diseases.

Glycan structures of glycoproteins and glycolipids on the surface glycocalyx and luminal sugar layers of intracellular membrane compartments in human cells constitute a key interface between intracellular biological processes and external environments. Sialic acids, a class of alpha-keto acid sugars with a nine-carbon backbone, are frequently found as the terminal residues of these glycoconjugates, forming the critical components of these sugar layers. Changes in the status and content of cellular sialic acids are closely linked to many human diseases such as cancer, cardiovascular, neurological, inflammatory, infectious, and lysosomal storage diseases. The molecular machineries responsible for the biosynthesis of the sialylated glycans, along with their biological interacting partners, are important therapeutic strategies and targets for drug development. The purpose of this article is to comprehensively review the recent literature and provide new scientific insights into the mechanisms and therapeutic implications of sialylation in glycoproteins and glycolipids across various human diseases. Recent advances in the clinical developments of sialic acid-related therapies are also summarized and discussed.

A Multiresponsive Ferrocene-Based Chiral Overcrowded Alkene Twisting Liquid Crystals.

The reversible modulation of chirality has gained significant attention not only for fundamental stereochemical studies but also for numerous applications ranging from liquid crystals (LCs) to molecular motors and machines. This requires the construction of switchable molecules with (multiple) chiral elements in a highly enantioselective manner, which is often a significant synthetic challenge. Here, we show that the dimerization of an easily accessible enantiopure planar chiral ferrocene-indanone building block affords a multi-stimuli-responsive dimer (FcD) with pre-determined double bond geometry, helical chirality, and relative orientation of the two ferrocene motifs in high yield. This intrinsically planar chiral switch can not only undergo thermal or photochemical E/Z isomerization but can also be reversibly and quantitatively oxidized to both a monocationic and a dicationic state which is associated with significant changes in its (chir)optical properties. Specifically, FcD acts as a chiral dopant for cholesteric LCs with a helical twisting power (HTP) of 13 μm-1 which, upon oxidation, drops to near zero, resulting in an unprecedently large redox-tuning of the LC reflection color by up to 84 nm. Due to the straightforward stereoselective synthesis, FcD, and related chiral switches, are envisioned to be powerful building blocks for multi-stimuli-responsive molecular machines and in LC-based materials.

A Multiresponsive Ferrocene‐Based Chiral Overcrowded Alkene Twisting Liquid Crystals

AbstractThe reversible modulation of chirality has gained significant attention not only for fundamental stereochemical studies but also for numerous applications ranging from liquid crystals (LCs) to molecular motors and machines. This requires the construction of switchable molecules with (multiple) chiral elements in a highly enantioselective manner, which is often a significant synthetic challenge. Here, we show that the dimerization of an easily accessible enantiopure planar chiral ferrocene‐indanone building block affords a multi‐stimuli‐responsive dimer (FcD) with pre‐determined double bond geometry, helical chirality, and relative orientation of the two ferrocene motifs in high yield. This intrinsically planar chiral switch can not only undergo thermal or photochemical E/Z isomerization but can also be reversibly and quantitatively oxidized to both a monocationic and a dicationic state which is associated with significant changes in its (chir)optical properties. Specifically, FcD acts as a chiral dopant for cholesteric LCs with a helical twisting power (HTP) of 13 μm−1 which, upon oxidation, drops to near zero, resulting in an unprecedently large redox‐tuning of the LC reflection color by up to 84 nm. Due to the straightforward stereoselective synthesis, FcD, and related chiral switches, are envisioned to be powerful building blocks for multi‐stimuli‐responsive molecular machines and in LC‐based materials.

Impact of molecular structure on the biological removal efficiency of fluoroquinolone antibiotics: An in-silico approach

Fluoroquinolone antibiotics (FQs), one of the most widely used antibacterials, have been recognized as emerging contaminants with adverse human health concerns. To overcome the adverse effects, a theoretical molecular design and screening approach was developed in this study to improve the removal efficiency of FQs by Chlorella in artificial or natural wetland systems. Among the 189 designed norfloxacin (NOR) derivatives, NOR-140 was screened with significantly improved biosorption, bioaccumulation, and biodegradation removal and functional effects, and reduced human health and ecological risks. The removal mechanism NOR-140 was also analyzed using adsorption kinetics, molecular docking, molecular dynamics simulations and machine learning models. Protein and polysaccharide structures play a major role in the adsorption process, polarizability and molecular volume of NOR-140 affect the bioaccumulation ability, and hydrogen bonding was found as the key force promoting the degradation ability of NOR-140. Modifying specific sites (5, 8, and 13) with functional groups containing highly electronegative atoms (O, F) significantly enhances the biodegradability of FQs alternatives by Chlorella. This study provided theoretical support for designing environmentally friendly FQs alternatives with improved degradation ability and advanced the understanding of how the FQs' molecular structures affect its removal by Chlorella.

Mayer-Homology Learning Prediction of Protein-Ligand Binding Affinities

Artificial intelligence-assisted drug design is revolutionizing the pharmaceutical industry. Effective molecular features are crucial for accurate machine learning predictions, and advanced mathematics plays a key role in designing these features. Persistent homology theory, which equips topological invariants with persistence, provides valuable insights into molecular structures. The standard homology theory is based on a differential rule for the boundary operator that satisfies [Formula: see text] = 0. Our recent work has extended this rule by employing Mayer homology with generalized differentials that satisfy [Formula: see text] = 0 for [Formula: see text] 2, leading to the development of persistent Mayer homology (PMH) theory and richer topological information across various scales. In this study, we utilize PMH to create a novel multiscale topological vectorization for molecular representation, offering valuable tools for descriptive and predictive analyses in molecular data and machine learning prediction. Specifically, benchmark tests on established protein-ligand datasets, including PDBbind-v2007, PDBbind-v2013, and PDBbind-v2016, demonstrate the superior performance of our Mayer homology models in predicting protein-ligand binding affinities.

Architectural dissection of adhesive bacterial cell surface appendages from a "molecular machines" viewpoint.

The ability of bacteria to interact with and respond to their environment is crucial to their lifestyle and survival. Bacterial cells routinely need to engage with extracellular target molecules, in locations spatially separated from their cell surface. Engagement with distant targets allows bacteria to adhere to abiotic surfaces and host cells, sense harmful or friendly molecules in their vicinity, as well as establish symbiotic interactions with neighboring cells in multicellular communities such as biofilms. Binding to extracellular molecules also facilitates transmission of information back to the originating cell, allowing the cell to respond appropriately to external stimuli, which is critical throughout the bacterial life cycle. This requirement of bacteria to bind to spatially separated targets is fulfilled by a myriad of specialized cell surface molecules, which often have an extended, filamentous arrangement. In this review, we compare and contrast such molecules from diverse bacteria, which fulfil a range of binding functions critical for the cell. Our comparison shows that even though these extended molecules have vastly different sequence, biochemical and functional characteristics, they share common architectural principles that underpin bacterial adhesion in a variety of contexts. In this light, we can consider different bacterial adhesins under one umbrella, specifically from the point of view of a modular molecular machine, with each part fulfilling a distinct architectural role. Such a treatise provides an opportunity to discover fundamental molecular principles governing surface sensing, bacterial adhesion, and biofilm formation.

Light, Switch, Action! The Influence of Geometrical Photoisomerization in an Adaptive Self-Assembled System.

The ubiquitous ability of natural dynamic nanostructures to adapt to environmental changes is a highly desirable property for chemical systems, particularly in the development of complex matter, molecular machines, and life-like materials. Designing such systems is challenging due to the generation of complex mixtures with responses that are difficult to predict, characterize, and diversify. Here, we navigate between self-assembled architectures using light by operating an intrinsic photoswitchable building block that governs the state of the system. When complementary units are present, the photoswitch determines the predominant architecture, reversibly adapting between the cage and macrocycles, including (otherwise inaccessible) higher-energy assemblies. Our study showcases this concept with seven different transformations, offering an unprecedented degree of control, diversification, and adaptation by self-selecting complementary units. These findings could enable applications of on-demand dissipative macrocycles based on dynamic bonds. We also envision different transient nanostructures, e.g., reticular and polymeric materials, being explored by fine-tuning the nature of the complementary unit.

Apicomplexan Espionage: Orchestrated Miscommunication at the Host-Parasite Interface.

Intracellular parasites, including Toxoplasma and Plasmodium, are entirely reliant on the active scavenging of host-derived nutrients to fuel their replicative cycle, as they are confined within a specialized membrane-bound compartment, the parasitophorous vacuole (PV). Initial observations, based on the proximity of host vesicles to the parasitophorous vacuole membrane (PVM), suggested that parasites utilize host vesicles to obtain essential nutrients. However, mounting evidence has now unequivocally demonstrated that intracellular pathogens establish membrane contacts with host organelles, establishing control over host cellular machinery. These intimate interactions enable the parasites to gain unimpeded access to cytosolic resources critical for development while evading host immune responses. This review consolidates the latest advancements in understanding the molecular machinery driving these transkingdom contacts and their functional roles. Further investigation into these processes promises to revolutionize our understanding of organelle communication, with profound implications for identifying new therapeutic targets and strategies.

The Drosophila adult midgut progenitor cells arise from asymmetric divisions of neuroblast-like cells.

The Drosophila adult midgut progenitor cells (AMPs) give rise to all cells in the adult midgut epithelium, including the intestinal stem cells (ISCs). While they share many characteristics with the ISCs, it remains unclear how they are generated in the early embryo. Here, we show that they arise from a population of endoderm cells, which exhibit multiple similarities with Drosophila neuroblasts. These cells, which we have termed endoblasts, are patterned by homothorax (Hth) and undergo asymmetric divisions using the same molecular machinery as neuroblasts. We also show that the conservation of this molecular machinery extends to the generation of the enteroendocrine lineages. Parallels have previously been drawn between the pupal ISCs and larval neuroblasts. Our results suggest that these commonalities exist from the earliest stages of specification of progenitor cells of the intestinal and nervous systems and may represent an ancestral pathway for multipotent progenitor cell specification.

Structure, Function and Engineering of the Nonribosomal Peptide Synthetase Condensation Domain.

The nonribosomal peptide synthetase (NRPS) is a highly precise molecular assembly machinery for synthesizing structurally diverse peptides, which have broad medicinal applications. Withinthe NRPS, the condensation (C) domain is a core catalytic domain responsible for the formation of amide bonds between individual monomer residues during peptide elongation. This review summarizes various aspects of the C domain, including its structural characteristics, catalytic mechanisms, substrate specificity, substrate gating function, and auxiliary functions. Moreover, through case analyses of the NRPS engineering targeting the C domains, the vast potential of the C domain in the combinatorial biosynthesis of peptide natural product derivatives is demonstrated.

Contraction rate estimates of stochastic gradient kinetic Langevin integrators

In previous work, we introduced a method for determining convergence rates for integration methods for the kinetic Langevin equation for M-▽Lipschitz m-log-concave densities [Leimkuhler et al., SIAM J. Numer. Anal. 62 (2024) 1226–1258]. In this article, we exploit this method to treat several additional schemes including the method of Brunger, Brooks and Karplus (BBK) and stochastic position/velocity Verlet. We introduce a randomized midpoint scheme for kinetic Langevin dynamics, inspired by the recent scheme of Bou-Rabee and Marsden [arXiv:2211.11003, 2022]. We also extend our approach to stochastic gradient variants of these schemes under minimal extra assumptions. We provide convergence rates of O(m/M), with explicit stepsize restriction, which are of the same order as the stability thresholds for Gaussian targets and are valid for a large interval of the friction parameter. We compare the contraction rate estimates of many kinetic Langevin integrators from molecular dynamics and machine learning. Finally, we present numerical experiments for a Bayesian logistic regression example.

Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome.

The spliceosome is the complex molecular machinery that sequentially assembles on eukaryotic messenger RNA precursors to remove introns (pre-mRNA splicing), a physiologically regulated process altered in numerous pathologies. We report transcriptome-wide analyses upon systematic knock down of 305 spliceosome components and regulators in human cancer cells and the reconstruction of functional splicing factor networks that govern different classes of alternative splicing decisions. The results disentangle intricate circuits of splicing factor cross-regulation, reveal that the precise architecture of late-assembling U4/U6.U5 tri-small nuclear ribonucleoprotein (snRNP) complexes regulates splice site pairing, and discover an unprecedented division of labor among protein components of U1 snRNP for regulating exon definition and alternative 5' splice site selection. Thus, we provide a resource to explore physiological and pathological mechanisms of splicing regulation.

RNA granules in flux: dynamics to balance physiology and pathology.

The life cycle of an mRNA is a complex process that is tightly regulated by interactions between the mRNA and RNA-binding proteins, forming molecular machines known as RNA granules. Various types of these membrane-less organelles form inside cells, including neurons, and contributecritically to various physiological processes. RNA granules are constantly in flux, change dynamically and adapt to their local environment, depending on their intracellular localization. The discovery that RNA condensates can form by liquid-liquid phase separation expanded our understanding of how compartments may be generated in the cell. Since then, a plethora of new functions have been proposed for distinct condensates in cells that await their validation in vivo. The finding that dysregulation of RNA granules (for example, stress granules) islikely toaffect neurodevelopmental and neurodegenerative diseases further boosted interest in this topic. RNA granules have various physiological functions in neurons and in the brain that we would like to focus on. We outline examples of state-of-the-art experiments including timelapse microscopy in neurons to unravel the precise functions of various types ofRNA granule. Finally, we distinguish physiologically occurring RNA condensation from aberrant aggregation, induced by artificial RNA overexpression, and present visual examples to discriminate both forms in neurons.

Formation and Stability of Benzylic Amide [2]- and [3]Rotaxanes: An Intercomponent Interactions Study.

One of the most recent focuses in supramolecular chemistry is developing molecules designed to exhibit programmable properties at the molecular level. Rotaxanes, which function as molecular machines with movements controlled by external stimuli, are prime candidates for this purpose. However, the controlled synthesis of rotaxanes, especially amide-benzylic rotaxanes with more than two components, remains an area ripe for exploration. In this study, we aim to elucidate the formation of amide-benzylic [3]rotaxanes using a thread that includes a conventional succinamide station and an innovative triazole-carbonyl station. Including the triazole-carbonyl station introduces new perspectives into the chemistry of rotaxanes, influencing their conformation and dynamics. The synthesis of two-station rotaxanes with varying stoppers demonstrated that the macrocycle consistently occupies the succinamide station, providing greater stability as evidenced by NMR and SC-XRD analyses. The presence of a triazole-carbonyl station facilitated the formation of a second macrocycle exclusively when a secondary amide was employed as the stopper group, presumably due to decreased steric hindrance. Moreover, the second macrocycle directly forms at the triazole-carbonyl station. This investigation reveals that slight modifications in the thread structure can dramatically impact the formation, stability, and interactions between components of rotaxanes.

Nanotechnology in pharmaceutical manufacturing: present innovations and future opportunities

Nanotechnology has revolutionized the pharmaceutical industry by enabling the design and delivery of drugs with enhanced precision, efficacy, and safety. This review provides a comprehensive overview of current trends and future prospects in nanotechnology-based drug manufacturing. It explores the application of nanocarriers, such as liposomes, micelles, and nanoparticles, which have improved drug bioavailability, targeted delivery, and reduced side effects. Nano formulations like solid lipid nanoparticles (SLNs) and polymeric nanoparticles are also highlighted for their role in controlled drug release and cancer treatment. Technological innovations, including advanced nanofabrication techniques and 3D printing, are driving the development of complex drug formulations. The review also addresses the challenges in scaling production and the evolving regulatory landscape. Future prospects include the use of nanobots and advanced Nano machines for drug delivery, the integration of nanotechnology in gene therapy and CRISPR, and the exploration of new research and investment opportunities. Ethical and safety considerations, such as the long-term effects of nanomaterials on human health and the environment, are discussed. This review underscores the transformative potential of nanotechnology in drug manufacturing, offering insights into its role in shaping the future of the pharmaceutical industry.

Bidirectional Molecular Motors by Controlling Threading and Dethreading Pathways of a Linked Rotaxane.

Artificial molecular motors have been presented as models for biological molecular motors. In contrast to the conventional artificial molecular motors that rely on covalent bond rotation, molecular motors with mechanically interlocked molecules (MIM) have attracted considerable attention owing to their ability to generate significant rotational motion by dynamically shuttling macrocyclic components. The topology of MIM-type rotational molecular motors is currently limited to catenane structures, which require intricate synthetic procedures that typically produce a low synthetic yield. In this study, we develop a novel class of MIM-type molecular motors with a rotaxane-type topology. The switching of the threading/dethreading pathways of the linked rotaxane by protecting/deprotecting the bulky stopper group and changing the solvent polarity enables a net unidirectional rotation of the molecular motor. The threading/dethreading reaction rates were quantitatively evaluated through detailed spectroscopic investigations. Repeated net unidirectional rotation and switching of the direction of rotation were also achieved. Our findings demonstrate that linked rotaxanes can serve as MIM-type molecular motors with reversible rotational direction controlled by threading/dethreading reactions. These motors hold potential as components of molecular machinery.

Bidirectional Molecular Motors by Controlling Threading and Dethreading Pathways of a Linked Rotaxane

AbstractArtificial molecular motors have been presented as models for biological molecular motors. In contrast to the conventional artificial molecular motors that rely on covalent bond rotation, molecular motors with mechanically interlocked molecules (MIMs) have attracted considerable attention owing to their ability to generate significant rotational motion by dynamically shuttling macrocyclic components. The topology of MIM‐type rotational molecular motors is currently limited to catenane structures, which require intricate synthetic procedures that typically produce a low synthetic yield. In this study, we develop a novel class of MIM‐type molecular motors with a rotaxane‐type topology. The switching of the threading/dethreading pathways of the linked rotaxane by protecting/deprotecting the bulky stopper group and changing the solvent polarity enables a net unidirectional rotation of the molecular motor. The threading/dethreading reaction rates were quantitatively evaluated through detailed spectroscopic investigations. Repeated net unidirectional rotation and switching of the direction of rotation were also achieved. Our findings demonstrate that linked rotaxanes can serve as MIM‐type molecular motors with reversible rotational direction controlled by threading/dethreading reactions. These motors hold potential as components of molecular machinery.