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At least 163 records · Page 9

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NASA NTRSDate not supplied

Systems Health Monitoring: Integrating FMEA into Bayesian Networks

The foreseeable high traffic density suggests that a large number of electric propulsion systems will enter the airspace, and that they will also operate at high frequency, e.g., large number of take offs and landings per unit time. The reliability of such critical systems is therefore key to ensure high safety standards in the low-altitude airspace. Diagnostic systems, which aim at identifying incipient faults, can mitigate unexpected failures or lower-than-expected reliability by performing early fault detection by monitoring the systems. A key element of fault diagnosis is fault detection and isolation (FDI), which complexity increases with the complexity of the system itself, namely the number of subsystems and components, interactions among sub-systems, and the number of sensors available. The proposed approach leverages combination of failure mode and effect analysis (FMEA) integrated with Bayesian networks, thus introducing dependability structures into a diagnostic framework to aid FDI. Faults and failure events from the FMEA are mapped within a Bayesian network, where network edges replicate the links embedded within FMEAs. The integrated framework enables the fault isolation process by identifying the probability of occurrence of specific faults or root causes given evidence observed through sensor signals. In this work, sub systems of Urban Air Mobility (UAM) type vehicle like avionics, structures, power-train etc. are taken into account to show the approach at the system level. This work integrates early design phase in the development of UAM type vehicles with diagnostic tools, which are often developed later in the product life-cycle, or retrofitted at a later time on systems. Failure mode and effect analysis (FMEA) derived for the system in the design phase is embedded within a Bayesian network (BN).

UAM↗

DOE OSTI2026

Measurements of the inert Hugoniot and observation of mechanical ignition in Ni(V) + Al reactive multilayers via x-ray diffraction

This study investigates the inert Hugoniot response, mechanical ignition, and reaction dynamics of Ni(V)+Al multilayers during longitudinal, laser-driven shock compression experiments. Ni(V)+Al multilayers, known for their self-propagating exothermic reactions, were subjected to longitudinal stresses exceeding 50 GPa using the laser shock facility within the Dynamic Compression Sector (DCS) at the Advanced Photon Source (APS). In situ x-ray diffraction (XRD) revealed that Ni(V) and Al were not in equilibrium during compression, with stress discrepancies attributed to twinning, grain structure effects, and/or dislocation density. However, the measured inert Hugoniot closely matched prior experimental and computational studies, confirming the utility of XRD for measuring the equation of state of thin, complex materials. Additionally, reaction was observed at significantly higher stresses than reported previously using laser-launched flyers. This discrepancy suggests a strong influence of externally imposed shear stress on reaction thresholds, which likely arose from deviations in flyer planarity during past experiments. Full reaction of the multilayer occurred within 40 ns after shock-wave passage, evidenced by complete melting of the constituents. Eulerian hydrocode simulations replicated experimental conditions, providing insights into equilibrium dynamics and experimental artifacts. The results highlight how even small shear forces facilitate ignition in Ni(V)+Al multilayers at lower stresses.

Crystallography↗

NASA NTRS2004

Hubble Space Telescope Degradation Data Used for Ground-Based Durability Projection of Insulation on the International Space Station

Ground-based environmental durability tests have indicated that exposing materials in accelerated tests to known spacecraft mission degradation sources predicted by an environmental model does not simulate the extent of damage that occurs in the space environment. The reasons for this may include the complex nature of the space environment, which is not simulated completely in any ground-based facility, the extreme differences in exposure rates in space and in ground tests, and inaccuracies in environmental models. One approach to overcoming the difficulties in simulating the space environment using ground-based testing is to calibrate the facility using data from actual space-exposed materials to determine exposure levels required to replicate degraded properties observed in space. Research was conducted at the NASA Glenn Research Center to develop a ground-to-space correlation method that determines the durability of Teflon-based insulation for the International Space Station (ISS) by using data obtained in a ground facility and degraded Teflon thermal insulation retrieved from the Hubble Space Telescope.

deGroh, Kim K.↗

DOE OSTI2024

Gold–Thiolate Nanocluster Dynamics and Intercluster Reactions Enabled by a Machine Learned Interatomic Potential

Monolayer protected metal clusters comprise a rich class of molecular systems and are promising candidate materials for a variety of applications. While a growing number of protected nanoclusters have been synthesized and characterized in crystalline forms, their dynamical behavior in solution, including prenucleation cluster formation, is not well understood due to limitations both in characterization and first-principles modeling techniques. Recent advancements in machine-learned interatomic potentials are rapidly enabling the study of complex interactions such as dynamical behavior and reactivity on the nanoscale. Here, we develop an Au-S-C-H atomic cluster expansion (ACE) interatomic potential for efficient and accurate molecular dynamics simulations of thiolate-protected gold nanoclusters (Au n (SCH 3 ) m ). Trained on more than 30,000 density functional theory calculations of gold nanoclusters, the interatomic potential exhibits ab initio level accuracy in energies and forces and replicates nanocluster dynamics including thermal vibration and chiral inversion. Long dynamics simulations (up to 0.1 μs time scale) reveal a mechanism explaining the thermal instability of neutral Au 25 (SR) 18 clusters. Specifically, we observe multiple stages of isomerization of the Au 25 (SR) 18 cluster, including a chiral isomer. Additionally, we simulate coalescence of two Au 25 (SR) 18 clusters and observe series of clusters where the formation mechanisms are critically mediated by ligand exchange in the form of [Au-S] n rings.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2025

HP-FLEX: Field demonstration of the semantics-driven configuration of a Model Predictive Control system to make heat pumps flexible

Model Predictive Control (MPC) has demonstrated significant potential for optimizing building operations and enabling demand flexibility. However, the widespread adoption of MPC is hindered by complex manual configuration and commissioning processes that must be conducted by control experts working alongside building operators. These challenges drive up costs and reduce scalability, particularly when technical human resources and building automation systems are limited, such as in small and medium commercial buildings (SMCBs). This paper demonstrates how semantic standards, specifically ASHRAE 223P, can accelerate the adoption of MPC applications for load flexibility in SMCBs. The authors present a replicable control framework, titled “HP-FLEX” that leverages a building’s semantic model to bootstrap the required data configuration for an MPC controller developed for optimizing heat pump systems as flexible grid resources. The semantic model helps streamline the deployment workflow, particularly for site setup, data/control commissioning, and model setup. This integration enhances portability, transferability, and scalability of the HP-FLEX MPC, which has been developed to support MPC-based supervisory HVAC controllers in SMCBs. Additionally, the paper details the required building and thermostat metadata information to enable the HP-FLEX MPC based on field demonstrations. The new workflow was tested in a small commercial building located in California, U.S., and demonstrated a load shifting performance of 9% based on a dynamic pricing signal that varies by the hour. This work provides a practical pathway for transitioning sophisticated building applications from custom to standardized semantic representations, supporting the broader adoption of advanced control strategies like MPC. The framework also establishes a foundation for evolving metadata requirements as applications mature while maintaining compatibility with industry standards.

Paul, Lazlo↗

DOE OSTI2025

HP-FLEX: Field Demonstration of the Semantics-Driven Configuration of a Model Predictive Control System to Make Heat Pumps Flexible

Paul, Lazlo↗

DOE OSTI2025

All-Atom Modeling and Simulation of Biopolymer Interface: Dual Role of Antifouling Polymer Brushes

Antifouling polymer brushes are well-known for their exceptional resistance to unwanted protein adsorption. While experimental studies have extensively characterized protein–polymer brush interactions, computational investigations remain limited, largely due to the challenges in accurately modeling and integrating these complex, multicomponent systems without resorting to oversimplification. To address this challenge, this study presents one of the most comprehensive and realistic model systems to date, comprising the substrate, grafted polymers, and proteins. Our work interprets the interactions between polymer brush and protein based on realistic modeling without simplification. In particular, this study utilizes molecular modeling and simulation of polycationic and polyzwitterionic brushes─poly(dimethylaminoethyl methacrylate) (PDMAEMA), poly(2-(N-oxide-N,N-dimethylamino)ethyl methacrylate) (PNOMA), and poly(2-(N-3-sulfopropyl-N,N-dimethylammonium)ethyl methacrylate) (PSBMA)─grafted onto α-quartz substrates via polymerization initiator linkers. The brush models were developed to closely replicate experimentally synthesized samples and to provide detailed insights into structural and dynamical changes at the molecular level during protein adsorption. Using steered molecular dynamics simulations, we show that the PSBMA brush, due to its high local density, exhibits the greatest resistance to protein insertion. Cα root-mean-square deviation and interaction pattern analyses further reveal that the PSBMA brush also induces the most significant destabilization of lysozyme, while the PDMAEMA brush enhances protein stability through ion-mediated interactions. The PNOMA brush, while requiring the lowest force for protein adsorption, induces greater protein destabilization than the PDMAEMA brush, primarily due to electrostatic repulsion caused by a short carbon spacer length. Hydration analysis reveals that both the PSBMA brush and the lysozyme interacting with it exhibit the most rapid dehydration, attributed to the brush’s high local chain density, which results in the greatest lysozyme destabilization and the highest adsorption force. These findings highlight the dual role of antifouling polymer brushes: resisting protein adsorption and modulating protein structural dynamics. In conclusion, this study provides valuable insights for the rational design of next-generation antifouling materials and offers a framework for realistic model development in complex multicomponent systems.

Adsorption↗

NASA NTRS1994

Experimental analysis of thread movement in bolted connections due to vibrations

The objective of this study was to identify the main design parameters contributing to loosening of bolts due to vibration and to identify their relative importance and degree of contribution to bolt loosening. Vibration testing was conducted on a shaketable with a controlled-random input in the dynamic testing laboratory of the Structural Test Division of MSFC. Test specimens which contained one test bolt were vibrated for a fixed amount of time and percentage of pre-load loss was measured. Each specimen tested implemented some combination of eleven design parameters as dictated by the design of experiment methodology employed. The eleven design parameters were: bolt size (diameter), lubrication on bolt, hole tolerance, initial pre-load, nut locking device, grip length, thread pitch, lubrication between mating materials, class of fit, joint configuration and mass of configuration. These parameters were chosen for this experiment because they are believed to be the design parameters having the greatest impact on bolt loosening. Two values of each design parameter were used and each combination of parameters tested was subjected to two different directions of vibration and two different g-levels of vibration. One replication was made for each test to gain some indication of experimental error and repeatability and to give some degree of statistical credibility to the data, resulting in a total of 96 tests being performed. The results of the investigation indicated that nut locking devices, joint configuration, fastener size, and mass of configuration were significant in bolt loosening due to vibration. The results of this test can be utilized to further research the complex problem of bolt loosening due to vibration.

Ramey, G. ED↗

NASA NTRS1995

Experimental analysis of thread movement in bolted connections due to vibrations

This is the final report of research project NAS8-39131 #33 sponsored by NASA's George C. Marshall Space Flight Center (MSFC) and carried out by the Civil Engineering Department of Auburn University (Auburn, Alabama) and personnel of MSFC. The objective of this study was to identify the main design parameters contributing to the loosening of bolts due to vibration and to identify their relative importance and degree of contribution to bolt loosening. Vibration testing was conducted on a shaketable with a controlled-random input in the dynamic testing laboratory of the Structural Test Division of MSFC. Test specimens which contained one test bolt were vibrated for a fixed amount of time and a percentage of pre-load loss was measured. Each specimen tested implemented some combination of eleven design parameters as dictated by the design of experiment methodology employed. The eleven design parameters were: bolt size (diameter), lubrication on bolt, hole tolerance, initial pre-load, nut locking device, grip length, thread pitch, lubrication between mating materials, class of fit, joint configuration, and mass of configuration. These parameters were chosen for this experiment because they are believed to be the design parameters having the greatest impact on bolt loosening. Two values of each design parameter were used and each combination of parameters tested was subjected to two different directions of vibration and two different g-levels of vibration. One replication was made for each test to gain some indication of experimental error and repeatability and to give some degree of statistical credibility to the data, resulting in a total of 96 tests being performed. The results of the investigation indicated that nut locking devices, joint configuration, fastener size, and mass of configuration were significant in bolt loosening due to vibration. The results of this test can be utilized to further research the complex problem of bolt loosening due to vibration.

Ramsey, G. ED↗

NASA NTRS1978

Automatic flight performance of a transport airplane on complex microwave landing system paths

During this demonstration the microwave landing system was utilized to provide the terminal configured vehicle B-737 airplane with guidance for automatic control on complex, curved descending paths with precision turns into short final approaches terminating in landing and roll-out, even when subjected to strong and gusty tail- and cross-wind components and severe wind shear. The data collected from more than fifty approach flights during the demonstration provided an opportunity to analyze airplane flight performance on a statistical basis rather than on a single flight record basis as is customarily done with limited data replication. Mean and standard deviation data are presented for approach flight path tracking parameters. In addition, the adverse wind conditions encountered during these flights are described using three-dimensional wind vector characteristics computed from the extensive on-board sensor data.

Walsh, T. M.↗

NASA NTRSDate not supplied

Particle Interaction Physics Model Formulation for Plume-Surface Interaction Erosion and Cratering

As part of the Game Changing Development (GCD) Program, funded by NASA’s Space Technology Mission Directorate (STMD), the development of simulation capability for the prediction of extra-terrestrial Plume Surface Interaction (PSI) environments has been undertaken by the Fluid Dynamics Branch at NASA/MSFC. The Predictive Simulation Capability (PSC) Element is focused on creating simulation capability for the reliable and accurate prediction of PSI in Martian (~650 Pa) and Lunar (vacuum) ambient environments. In addition to the predictive simulation capability, the GCD Program also contains a companion Ground Testing Element for development of focused datasets for validation of predictive capability as well as a Flight-focused Instrumentation Element. This paper will present the status of implementing and maturing particle-particle interaction constituent physics models essential in simulating the landing surface granular material flow under PSI effects. This gas-particle multi-phase interaction modeling of plume impingement flow on the extra-terrestrial soil material is performed with the Gas-Granular Flow Solver (GGFS) addressed in a companion paper. The response of regolith particle flow induced by lander PSI requires accurate representation of the regolith granular material fluidic behavior and gas-granular interactions. The lunar regolith, as the extreme example, is poorly sorted with broad particle size distributions and large fines content. It has significant cohesion, due to interlocking particle shapes for the very jagged particles. The combination of particle shape and size distribution has been identified as major drivers in the complex particle flow response and resulting crater shape characteristics of extraterrestrial granular material. Constituent models for spherical particles can be formulated directly from particle kinetics theory. Complex particle shapes can be modeled by gluing together elemental spherical shapes into composite particles, requiring a Discrete Element Model (DEM) particle kinetics modeling approach to extract data and formulate constituent models. Mixture constituent models for poly-disperse mixtures (i.e, containing distribution of particle sizes) have recently been developed. The required non-spherical particle mixture granular material response closure models are then obtained through small-scale unit physics DEM simulations for the range of particle shapes, mixtures and packing densities. The granular material response closure models are then implemented in the Eulerian granular flow formulation. This DEM-based constituent model extraction process and formulation of poly-disperse particle mixtures has been successfully developed by small business and academic partners in the development of the Gas-Granular Flow Solver (GGFS) simulation program simulation framework. The currently implemented capabilities have reached the capability level of modeling bi-disperse, non-spherical particle mixtures is being continuously extended towards computational modeling of full range irregular particle mixtures. Under the GCD project, this technology is being further developed, transferred to NASA analysts, and matured towards application readiness. The predictive simulation capability team under the GCD project has acquired the modeling tools and processes of the DEM based constituent model formulation from the GGFS development team and is developing the capability to replicate the existing process. This is the first important step towards the ability of the NASA team to independently perform such model development in a production setting. Further efforts are underway to migrate the DEM based model simulation process performed with the academic based tools to more capable Open Source, highly parallelized simulation tools for efficient operation on NASA HPC assets. Evaluation of the currently implemented (such as mono-disperse and bi-disperse spherical and irregular shape particle constituent model applications) and continuously evolving full-range particle physics models in the GGFS tool is performed by the NASA team to advance application readiness of the simulations. Application testing for complex PSI erosions and cratering scenarios such as the Apollo LM is performed for axi-symmetric and full 3D simulations to aid the tool developers in achieving practical application readiness for NASA projects. Important validation and application testing will further be performed against experimental data generated under the GCD PSI project experimental component.

Peter A Liever↗

NASA NTRS2008

Safety Critical Mechanisms

Spaceflight mechanisms have a reputation for being difficult to develop and operate successfully. This reputation is well earned. Many circumstances conspire to make this so: the environments in which the mechanisms are used are extremely severe, there is usually limited or no maintenance opportunity available during operation due to this environment, the environments are difficult to replicate accurately on the ground, the expense of the mechanism development makes it impractical to build and test many units for long periods of time before use, mechanisms tend to be highly specialized and not prone to interchangeability or off-the-shelf use, they can generate and store a lot of energy, and the nature of mechanisms themselves, as a combination of structures, electronics, etc. designed to accomplish specific dynamic performance, makes them very complex and subject to many unpredictable interactions of many types. In addition to their complexities, mechanism are often counted upon to provide critical vehicle functions that can result in catastrophic events should the functions not be performed. It is for this reason that mechanisms are frequently subjected to special scrutiny in safety processes. However, a failure tolerant approach, along with good design and development practices and detailed design reviews, can be developed to allow such notoriously troublesome mechanisms to be utilized confidently in safety-critical applications.

Robertson, Brandan↗

NASA NTRS1997

CCAAT/enhancer-binding protein delta activates insulin-like growth factor-I gene transcription in osteoblasts. Identification of a novel cyclic AMP signaling pathway in bone

Insulin-like growth factor-I (IGF-I) plays a key role in skeletal growth by stimulating bone cell replication and differentiation. We previously showed that prostaglandin E2 (PGE2) and other cAMP-activating agents enhanced IGF-I gene transcription in cultured primary rat osteoblasts through promoter 1, the major IGF-I promoter, and identified a short segment of the promoter, termed HS3D, that was essential for hormonal regulation of IGF-I gene expression. We now demonstrate that CCAAT/enhancer-binding protein (C/EBP) delta is a major component of a PGE2-stimulated DNA-protein complex involving HS3D and find that C/EBPdelta transactivates IGF-I promoter 1 through this site. Competition gel shift studies first indicated that a core C/EBP half-site (GCAAT) was required for binding of a labeled HS3D oligomer to osteoblast nuclear proteins. Southwestern blotting and UV-cross-linking studies showed that the HS3D probe recognized a approximately 35-kDa nuclear protein, and antibody supershift assays indicated that C/EBPdelta comprised most of the PGE2-activated gel-shifted complex. C/EBPdelta was detected by Western immunoblotting in osteoblast nuclear extracts after treatment of cells with PGE2. An HS3D oligonucleotide competed effectively with a high affinity C/EBP site from the rat albumin gene for binding to osteoblast nuclear proteins. Co-transfection of osteoblast cell cultures with a C/EBPdelta expression plasmid enhanced basal and PGE2-activated IGF-I promoter 1-luciferase activity but did not stimulate a reporter gene lacking an HS3D site. By contrast, an expression plasmid for the related protein, C/EBPbeta, did not alter basal IGF-I gene activity but did increase the response to PGE2. In osteoblasts and in COS-7 cells, C/EBPdelta, but not C/EBPbeta, transactivated a reporter gene containing four tandem copies of HS3D fused to a minimal promoter; neither transcription factor stimulated a gene with four copies of an HS3D mutant that was unable to bind osteoblast nuclear proteins. These results identify C/EBPdelta as a hormonally activated inducer of IGF-I gene transcription in osteoblasts and show that the HS3D element within IGF-I promoter 1 is a high affinity binding site for this protein.

NASA Discipline Musculoskeletal↗

NASA NTRS2002

Piloted Evaluation of a UH-60 Mixer Equivalent Turbulence Simulation Model

A simulation study of a recently developed hover/low speed Mixer Equivalent Turbulence Simulation (METS) model for the UH-60 Black Hawk helicopter was conducted in the NASA Ames Research Center Vertical Motion Simulator (VMS). The experiment was a continuation of previous work to develop a simple, but validated, turbulence model for hovering rotorcraft. To validate the METS model, two experienced test pilots replicated precision hover tasks that had been conducted in an instrumented UH-60 helicopter in turbulence. Objective simulation data were collected for comparison with flight test data, and subjective data were collected that included handling qualities ratings and pilot comments for increasing levels of turbulence. Analyses of the simulation results show good analytic agreement between the METS model and flight test data, with favorable pilot perception of the simulated turbulence. Precision hover tasks were also repeated using the more complex rotating-frame SORBET (Simulation Of Rotor Blade Element Turbulence) model to generate turbulence. Comparisons of the empirically derived METS model with the theoretical SORBET model show good agreement providing validation of the more complex blade element method of simulating turbulence.

Lusardi, Jeff A.↗

DOE OSTI2025

Structure of coxsackievirus cloverleaf RNA and 3C pro dimer establishes the RNA-binding mechanism of enterovirus protease 3C pro

In positive-strand RNA viruses, the genome serves as a template for both protein translation and negative-strand RNA synthesis. Enteroviruses use the cloverleaf RNA structure at the 5′ end of the genome to balance these two processes. Cloverleaf acts as a promoter for RNA synthesis and forms a complex with viral 3CD protein, the precursor to 3C pro protease, and 3D pol polymerase. The interaction between cloverleaf and 3CD is mediated by the 3C pro domain, yet how 3C pro promotes specific RNA-binding is not clear. We report the structure of coxsackievirus cloverleaf RNA-3C pro complex, wherein two 3C pro molecules interact with cloverleaf stem-loop D. 3C pro dimer mainly recognizes the shape of the dsRNA helix through symmetric interactions, suggesting that 3C pro is a previously undiscovered type of RNA binding protein. We show that 3CD protein also dimerizes on cloverleaf RNA and binds the RNA with higher affinity than 3C pro . The structure provides insight into the RNA-binding mechanism of 3C pro or 3CD with other cis-acting replication elements.

Science & Technology - Other Topics↗

NASA NTRS1995

Mode Transitions in Glass Cockpit Aircraft: Results of a Field Study

One consequence of increased levels of automation in complex control systems is the presence of modes. A mode is a particular configuration of a control system that defines how human command inputs are interpreted. In complex systems, modes also often determine a specific allocation of control authority between the human and automated systems. Even in simple static devices (e.g., electronic watches, word processors), the presence of modes has been found to cause problems in either-the acquisition or production of skilled performance. Many of these problems arise due to the fact that the selection of a mode causes device behavior to be mediated by hidden internal state information. For these simple systems, many of these interaction problems can be solved by the design of appropriate feedback to communicate internal state information to the human operator. In complex dynamic systems, however, the design issues associated with modes seem to trancend the problem of merely communicating internal state information via displayed feedback. In complex supervisory control systems (e.g., aircraft, spacecraft, military command and control), a key function of modes is the selection of a particular configuration of control authority between the human operator and automated control systems. One mode may result in full manual control, another may result in a mix of manual and automatic control, while a third may result in full automatic control over the entire system. The human operator selects an appropriate mode as a function of current goals, operating conditions, and operating procedures. Thus, the operator is put in a position of essentially trying to control two coupled dynamic systems: the target system itself, and also a highly complex suite of automation controlling the target system. From a historical perspective, it should probably not come as a surprise that very little information is available to guide the design of mode-oriented control systems. The topic of function allocation (i.e., the proper division of control authority among human and computer) has a long history in human-machine systems research. Although this research has produced some relevant guidelines, a design approach capable of defining appropriate allocations of control function between the human and automation is not yet available. As a result, the function allocation decision itself has been allocated to the operator, to be performed in real-time, in the operation of mode-oriented control systems. A variety of documented aircraft accidents and incidents suggest that the real-time selection and monitoring of control modes is a weak link in the effective operation of complex supervisory control systems. Research in human-machine systems and human-computer interaction has barely scraped the surface of the problem of understanding how operators manage this task.The purpose of this paper is to present the results of a field study which examined how operators manage mode selection in a complex supervisory control system. Data on mode engagements using the Boeing B757/767 auto-flight system were collected during approach and descent into four major airports in the East Coast of the United States. Protocols documenting mode selection, automatic mode changes, pilot actions, quantitative records of flight-path variables, and verbal reports during and after mode engagements were collected by an observer from the jumpseat. Observations were conducted on two typical trips between three airports. Each trip was be replicated 11 times, which yielded a total of 22 trips and 66 legs on which data were collected. All data collected concerned the same flight numbers, and therefore, the same time of day, same type of aircraft, and identical operational environments (e.g., ATC facilities, weather patterns, traffic flow etc.)

Degani, Asaf↗

NASA NTRS1997

Entropy and charge in molecular evolution--the case of phosphate

Biopoesis, the creation of life, implies molecular evolution from simple components, randomly distributed and in a dilute state, to form highly organized, concentrated systems capable of metabolism, replication and mutation. This chain of events must involve environmental processes that can locally lower entropy in several steps; by specific selection from an indiscriminate mixture, by concentration from dilute solution, and in the case of the mineral-induced processes, by particular effectiveness in ordering and selective reaction, directed toward formation of functional biomolecules. Numerous circumstances provide support for the notion that negatively charged molecules were functionally required and geochemically available for biopoesis. Sulfite ion may have been important in bisulfite complex formation with simple aldehydes, facilitating the initial concentration by sorption of aldehydes in positively charged surface active minerals. Borate ion may have played a similar, albeit less investigated role in forming charged sugar complexes. Among anionic species, oligophosphate ions and charged phosphate esters are likely to have been of even more wide ranging importance, reflected in the continued need for phosphate in a proposed RNA world, and extending its central role to evolved biochemistry. Phosphorylation is shown to result in selective concentration by surface sorption of compounds, otherwise too dilute to support condensation reactions. It provides protection against rapid hydrolysis of sugars and, by selective concentration, induces the oligomerization of aldehydes. As a manifestation of life arisen, phosphate already appears in an organic context in the oldest preserved sedimentary record.

NASA Discipline Exobiology↗

DOE OSTI2025

Influence of Steric and Electronic Properties of P2 Groups on Covalent Inhibitor Binding to SARS-CoV-2 Main Protease

The main protease (MPro) of SARS-CoV-2 is a critical enzyme required for viral replication, making it a prime target for antiviral drug development. Covalent inhibitors, which form a stable interaction with the catalytic C145, have demonstrated strong inhibition of MPro, but the influence of steric and electronic properties of P2 substituents, designed to engage the S2 substrate-binding subsite within the MPro active site, on inhibitor binding affinity remains underexplored. Here, in this study, we design and characterize two hybrid covalent inhibitors, BBH-3 and BBH-4, and present their X-ray crystallographic structures in complex with MPro, providing molecular insights into how their distinct P2 groups, a dichlorobenzyl moiety in BBH-3 and an adamantyl substituent in BBH-4, affect binding conformation and active site adaptability. Comparative structural analyses with previously characterized inhibitors, including BBH-2 and Mcule-5948770040, reveal how the P2 bulkiness and electronic properties influence active site dynamics, particularly through interactions with the S2 and S5 subsites. The P2 group of BBH-3 induces conformational shifts in the S2 helix and the S5 loop, while BBH-4 displaces M49, stabilizing its binding through hydrophobic interactions. Isothermal titration calorimetry further elucidates the impact of P2 modifications on inhibitor affinity, revealing a delicate balance between enthalpic and entropic contributions. The data demonstrate that BBH-3 exhibits less favorable binding, affirming that dichlorobenzyl substitution at the P2 position has a more negative impact on the affinity for MPro than bulky saturated cyclic groups. This underscores the feature that MPro active site malleability may be accompanied by a conformational strain.

SARS-CoV-2↗