SEARCH · Engineering Papers

Results for “human dynamics”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,261 records · Page 70

All sources NASA NTRS DOE OSTI

NASA NTRS2012

Identification of Time-Varying Pilot Control Behavior in Multi-Axis Control Tasks

Recent developments in fly-by-wire control architectures for rotorcraft have introduced new interest in the identification of time-varying pilot control behavior in multi-axis control tasks. In this paper a maximum likelihood estimation method is used to estimate the parameters of a pilot model with time-dependent sigmoid functions to characterize time-varying human control behavior. An experiment was performed by 9 general aviation pilots who had to perform a simultaneous roll and pitch control task with time-varying aircraft dynamics. In 8 different conditions, the axis containing the time-varying dynamics and the growth factor of the dynamics were varied, allowing for an analysis of the performance of the estimation method when estimating time-dependent parameter functions. In addition, a detailed analysis of pilots adaptation to the time-varying aircraft dynamics in both the roll and pitch axes could be performed. Pilot control behavior in both axes was significantly affected by the time-varying aircraft dynamics in roll and pitch, and by the growth factor. The main effect was found in the axis that contained the time-varying dynamics. However, pilot control behavior also changed over time in the axis not containing the time-varying aircraft dynamics. This indicates that some cross coupling exists in the perception and control processes between the roll and pitch axes.

Zaal, Peter M. T.↗

NASA NTRS2014

A Study of Future Communications Concepts and Technologies for the National Airspace System-Part III

The National Aeronautics and Space Administration (NASA) Glenn Research Center (GRC) is investigating current and anticipated wireless communications concepts and technologies that the National Airspace System (NAS) may need in the next 50 years. NASA has awarded three NASA Research Announcements (NAR) studies with the objective to determine the most promising candidate technologies for air-to-air and air-to-ground data exchange and analyze their suitability in a post-NextGen NAS environment. This paper will present progress made in the studies and describe the communications challenges and opportunities that have been identified as part of the study. NASA's NextGen Concepts and Technology Development (CTD) Project integrates solutions for a safe, efficient and high-capacity airspace system through joint research efforts and partnerships with other government agencies. The CTD Project is one of two within NASA's Airspace Systems Program and is managed by the NASA Ames Research Center. Research within the CTD Project is in support the 2011 NASA Strategic Plan Sub-Goal 4.1: Develop innovative solutions and advanced technologies, through a balanced research portfolio, to improve current and future air transportation. The focus of CTD is on developing capabilities in traffic flow management, dynamic airspace configuration, separation assurance, super density operations and airport surface operations. Important to its research is the development of human/automation information requirements and decisionmaking guidelines for human-human and human-machine airportal decision-making. Airborne separation, oceanic intrail climb/descent and interval management applications depend on location and intent information of surrounding aircraft. ADS-B has been proposed to provide the information exchange, but other candidates such as satellite-based receivers, broadband or airborne internet, and cellular communications are possible candidate's.

Navigation↗

NASA NTRS2016

Unmanned Aerial Systems Traffic Management (UTM): Safely Enabling UAS Operations in Low-Altitude Airspace

Currently, there is no established infrastructure to enable and safely manage the widespread use of low-altitude airspace and UAS flight operations. Given this, and understanding that the FAA faces a mandate to modernize the present air traffic management system through computer automation and significantly reduce the number of air traffic controllers by FY 2020, the FAA maintains that a comprehensive, yet fully automated UAS traffic management (UTM) system for low-altitude airspace is needed. The concept of UTM is to begin by leveraging concepts from the system of roads, lanes, stop signs, rules and lights that govern vehicles on the ground today. Building on its legacy of work in air traffic management (ATM), NASA is working with industry to develop prototype technologies for a UAS Traffic Management (UTM) system that would evolve airspace integration procedures for enabling safe, efficient low-altitude flight operations that autonomously manage UAS operating in an approved low-altitude airspace environment. UTM is a cloud-based system that will autonomously manage all traffic at low altitudes to include UASs being operated beyond visual line of sight of an operator. UTM would thus enable safe and efficient flight operations by providing fully integrated traffic management services such as airspace design, corridors, dynamic geofencing, severe weather and wind avoidance, congestion management, terrain avoidance, route planning re-routing, separation management, sequencing spacing, and contingency management. UTM removes the need for human operators to continuously monitor aircraft operating in approved areas. NASA envisions concepts for two types of UTM systems. The first would be a small portable system, which could be moved between geographical areas in support of operations such as precision agriculture and public safety. The second would be a Persistent system, which would support low-altitude operations in an approved area by providing continuous automated coverage. Both would require persistent communication, navigation, and surveillance (CNS) coverage to track, ensure, and monitor conformance. UTM is creating an airspace management tool that allows the ATM system to accommodate the number of UAS that will operate in the low altitude airspace. The analogy is just because we have a car, whether its autonomous or someone is driving, does not diminish the need for a road or road signs or rules of the road.

traffic management↗

NASA NTRSDate not supplied

Computational Analysis of a Multiple-Nozzle Supersonic Retropropulsion Configuration

Supersonic retropropulsion is an enabling capability to land large payloads on the surface of Mars. The retropropulsion flowfield is a highly dynamic environment with strong shocks, free shear layers, and plumes opposing high-speed flow. For flight vehicles with large aerodynamic surface area, such as NASA concepts for human Mars exploration, retropropulsion can induce significant aerodynamic interference forces and moments on the vehicle during powered flight. A multiple-nozzle configuration from upcoming, inert gas, sub-scale, supersonic wind tunnel testing is simulated at Mach 2.4 conditions for angles of attack of 0 and 10 degrees and thrust coefficients of 0.5, 1.0, and 2.5. This paper examines changes in the resulting flowfield, surface pressures, and integrated forces with thrust force coefficient and angle of attack using a Detached Eddy Simulation approach.

retropropulsion↗

NASA NTRSDate not supplied

Closed-Loop Simulations of Human-Scale Mars Lander Descent Trajectories on Frontier

A computational campaign was performed to run high-fidelity, free-flight simulations of a human-scale Mars lander concept vehicle decelerating under retropropulsion through the Martian atmosphere with closed-loop flight control. A novel approach is used to couple computational fluid dynamics (CFD) software with a mature flight mechanics package, where the two applications communicate in real-time across two geographically-dispersed computational facilities. The CFD is performed on the Frontier exascale system located at Oak Ridge National Laboratory, and the flight mechanics are executed on a system located at NASA Langley Research Center. In the current campaign, CFD is performed using finite-rate chemistry to account for the interactions between the LOXCH 4 engines and the CO 2 Martian atmosphere. A simulation of a closed-loop main engine throttling and RCS actuation is presented, demonstrating that the vehicle and model are able to maintain stability in a long-duration CFD-in-the-loop flight simulation. Comparisons are made to a reduced order model ignoring aero-propulsive interactions.

CFD↗

NASA NTRS2007

Second Cancers After Fractionated Radiotherapy: Stochastic Population Dynamics Effects

When ionizing radiation is used in cancer therapy it can induce second cancers in nearby organs. Mainly due to longer patient survival times, these second cancers have become of increasing concern. Estimating the risk of solid second cancers involves modeling: because of long latency times, available data is usually for older, obsolescent treatment regimens. Moreover, modeling second cancers gives unique insights into human carcinogenesis, since the therapy involves administering well characterized doses of a well studied carcinogen, followed by long-term monitoring. In addition to putative radiation initiation that produces pre-malignant cells, inactivation (i.e. cell killing), and subsequent cell repopulation by proliferation can be important at the doses relevant to second cancer situations. A recent initiation/inactivation/proliferation (IIP) model characterized quantitatively the observed occurrence of second breast and lung cancers, using a deterministic cell population dynamics approach. To analyze ifradiation-initiated pre-malignant clones become extinct before full repopulation can occur, we here give a stochastic version of this I I model. Combining Monte Carlo simulations with standard solutions for time-inhomogeneous birth-death equations, we show that repeated cycles of inactivation and repopulation, as occur during fractionated radiation therapy, can lead to distributions of pre-malignant cells per patient with variance >> mean, even when pre-malignant clones are Poisson-distributed. Thus fewer patients would be affected, but with a higher probability, than a deterministic model, tracking average pre-malignant cell numbers, would predict. Our results are applied to data on breast cancers after radiotherapy for Hodgkin disease. The stochastic IIP analysis, unlike the deterministic one, indicates: a) initiated, pre-malignant cells can have a growth advantage during repopulation, not just during the longer tumor latency period that follows; b) weekend treatment gaps during radiotherapy, apart from decreasing the probability of eradicating the primary cancer, substantially increase the risk of later second cancers.

Sachs, Rainer K.↗

NASA NTRS2017

Vascular Patterning Analysis by VESGEN 2D/3D with Bioinformatics: Updates for Rodent Tissues

Fractally branching vascular systems are a complex physiological requirement shared by humans with all higher terrestrial life forms, including other vertebrates, insects, and higher land plants. Vascular trees, networks, and tree-network composites are therefore mapped and quantified by the VESsel GENeration Analysis (VESGEN) software according to weighted physiological vascular rules that include vessel connectivity, tapering and bifurcational branching. According to fluid dynamics, successful vascular transport depends upon a complex distributed system of highly regulated laminar flow. VESGEN has elucidated changes in vascular patterning resulting from inflammatory, developmental and other signaling pathways within numerous tissues of major model organisms important for Space Biology, especially for rodents. Important early stage regenerative opportunities have been identified by VESGEN vascular analysis for visual impairments in the human retina, and is currently being used for research into astronaut visual and ocular disorders associated with long duration missions. The VESGEN 2D software is a mature, automated, widely published capability for which beta testing and public release by NASA is planned for the upcoming year. Early-stage capabilities for VESGEN 3D analysis are under development for the rodent retina and intestine as prototype tissues. A prototype VESGEN 2D Bioinformatics software capability has also been developed to associate phenotypic changes in molecular expression with vascular structure and function. By new VESGEN bioinformatic innovations, expression patterns of the genetic, transcriptional, protein and other markers for regulatory molecules such as vascular endothelial growth factor (VEGF) and their receptors, often indicators of tissue oxygenation status, are co-localized with alterations in vascular pattern. Biomarkers are therefore mapped and quantified as information dimensions directly correlated with the spatial dimensions of a vascular pattern. Further important technology innovations by NASA include substantial image segmentation advances for more automated binary extraction of the grayscale vascular patterns, together with informative associated image quality assessments. Vascular mapping and quantification capabilities for the rodent retina and intestine are illustrated for VESGEN 2D, along with technology status reports on VESGEN 3D and Bioinformatic capabilities. Research partially supported by Ames Center Innovation Awards.

Parsons-Wingerter, P.↗

DOE OSTI2025

From Obsolete to Optimal (ATR Demineralized Water System)

My project was migrating a Human-Machine Interface (HMI) and Programmable Logic Controller (PLC) program from legacy software to a modern platform, enhancing operational efficiency and eliminating unsupported, obsolete equipment. Initially, I used a migration tool to transfer the programs to the new software, then manually updated variables to align with the new PLC. I optimized the PLC code by leveraging new scaling features in the I/O cards, removing over 45 obsolete rungs, and enhancing clarity with functional tag aliases. Next, I modernized the HMI's visuals with an updated color scheme and 3D buttons. I developed multiple interface versions iteratively refining them based on operator feedback. I also designed and created a dedicated "Rounds" screen incorporating insights from a previous intern’s project to streamline daily rounds. To improve clarity, consistency, and efficiency I redesigned the entire interface. Adding visual indicators to enhance operational awareness: red is used for values outside normal specifications, green for normal operating modes, yellow for manual mode, and grey for offline units. Additionally, I added a dynamic visual representation of tank levels, creating PLC logic to show the level in inches as well as inches and feet. I then incorporated a navigation sidebar to facilitate efficient screen transitions. Risk of human error was mitigated by defining narrow input ranges for tank level shutoff and password protecting setpoint changes. I also fixed issues with datatypes that caused inaccuracies in the original code. Overall, this comprehensive upgrade significantly enhanced the HMI's functionality, user experience, and operational reliability.

47 - OTHER INSTRUMENTATION↗

NASA NTRS1990

Results from teleoperated free-flying spacecraft simulations in the Martin Marietta space operations simulator lab

To augment the capabilities of the Space Transportation System, NASA has funded studies and developed programs aimed at developing reusable, remotely piloted spacecraft and satellite servicing systems capable of delivering, retrieving, and servicing payloads at altitudes and inclinations beyond the reach of the present Shuttle Orbiters. Since the mid 1970's, researchers at the Martin Marietta Astronautics Group Space Operations Simulation (SOS) Laboratory have been engaged in investigations of remotely piloted and supervised autonomous spacecraft operations. These investigations were based on high fidelity, real-time simulations and have covered a wide range of human factors issues related to controllability. Among these are: (1) mission conditions, including thruster plume impingements and signal time delays; (2) vehicle performance variables, including control authority, control harmony, minimum impulse, and cross coupling of accelerations; (3) maneuvering task requirements such as target distance and dynamics; (4) control parameters including various control modes and rate/displacement deadbands; and (5) display parameters involving camera placement and function, visual aids, and presentation of operational feedback from the spacecraft. This presentation includes a brief description of the capabilities of the SOS Lab to simulate real-time free-flyer operations using live video, advanced technology ground and on-orbit workstations, and sophisticated computer models of on-orbit spacecraft behavior. Sample results from human factors studies in the five categories cited above are provided.

Hartley, Craig S.↗

NASA NTRSDate not supplied

Investigating Risks Due to Artemis EVA Tempo Via Probabilistic Risk Assessment

Spaceflight operations pose unique challenges to crew health, safety, and resource management. As space agencies and private companies continue to push the boundaries of human exploration, it is essential to understand the risks associated with Extravehicular Activities (EVAs) and develop strategies to mitigate them. The tempo at which EVAs are conducted – the total number and frequency of these activities – can have a profound impact on medical risks, resource consumption, and overall mission success. Probabilistic risk assessment (PRA) provides a powerful framework for evaluating complex systems and identifying potential hazards. Our work employs the Medical Extensible Dynamic Probabilistic Risk Assessment Tool (MEDPRAT) [1] to simulate mission events, occurrence and treatment of medical conditions, and track the utilization of resources. Coupled with the Evidence Library [2], a medical evidence base for exploration-class missions developed by the Exploration Medical Capability within NASA’s Human Research Program, we can estimate these risks with increased fidelity and optimize medical kit contents to meet specific mission requirements. This presentation provides a detailed examination of how EVA tempo influences medical risk estimates for a lunar surface design reference mission. A comprehensive analysis is conducted to assess the additional mass and volume burden imposed on medical kits required to maintain adequate levels of risk mitigation. Furthermore, we estimate the distribution of the number of successful EVAs completed based on the level of task impairment imposed by medical events and flight rules related to specific medical events, such as decompression sickness.

Modeling↗

NASA NTRSDate not supplied

Composition Reanalyses at NASA’s Global Modeling and Assimilation Office

Scientific Assessments of Ozone Depletion 2018 and 2022 report the recovery of Antarctic ozone, consistent with diminishing concentrations of halogens in the stratosphere. Both the size and the depth of the springtime ozone holes exhibit downward trends, particularly in September. Superimposed on the recovery trend are significant year-to-year fluctuations arising from dynamical variability potentially influenced by climate forcing and volcanic eruptions. Since 2018 the Antarctic stratosphere has experienced a wild parade of austral spring seasons with a sudden stratospheric warming and exceptionally high ozone in 2019 followed by large and long-lasting ozone holes in the following years, prompting questions about the speed and detectability of Antarctic ozone recovery and its potential connections to human-induced climate change. From the Australian New Years’ wildfires of 2020 to volcanic aerosols to the unprecedented injection of water vapor by the Hunga volcanic eruption, recent scientific literature on the subject investigates many factors that may or may not have contributed to this remarkable interannual variability. This presentation summarizes dynamical influences on springtime Antarctic stratospheric ozone in recent years and discusses these results in the context of long-term trends. In particular, this work seeks to isolate dynamical and chemical contributions to the Antarctic springs since 2019 using a consistent methodological framework. Our analysis uses constituent and meteorological fields from the MERRA-2 Stratospheric Composition Reanalysis of Aura MLS (M2-SCREAM) in combination with data from the Atmospheric Chemistry Experiment – Fourier Transform Spectrometer and from ozone sondes. Using the high spatial and temporal resolution of M2-SCREAM, we analyze the daily evolution of southern polar ozone, HCl, N2O, and water vapor in dynamical flow-following coordinates relative to the location, size, and shape of the polar vortex. For vertically integrated stratospheric ozone we emphasize the importance of the wave-influenced geometry of the polar vortex and its vertical alignment. The ultimate purpose of this project is to contribute to the quantification of the speed of the Antarctic ozone recovery and associated uncertainties.

Krzysztof Wargan↗

NASA NTRS1991

User interface issues in supporting human-computer integrated scheduling

The topics are presented in view graph form and include the following: characteristics of Operations Mission Planner (OMP) schedule domain; OMP architecture; definition of a schedule; user interface dimensions; functional distribution; types of users; interpreting user interaction; dynamic overlays; reactive scheduling; and transitioning the interface.

Cooper, Lynne P.↗

NASA NTRS2016

Unmanned Aircraft Systems Traffic Management (UTM) Safely Enabling UAS Operations in Low-Altitude Airspace

Unmanned Aircraft System (UAS) Traffic Management (UTM) Enabling Civilian Low-Altitude Airspace and Unmanned Aircraft System Operations What is the problem? Many beneficial civilian applications of UAS have been proposed, from goods delivery and infrastructure surveillance, to search and rescue, and agricultural monitoring. Currently, there is no established infrastructure to enable and safely manage the widespread use of low-altitude airspace and UAS operations, regardless of the type of UAS. A UAS traffic management (UTM) system for low-altitude airspace may be needed, perhaps leveraging concepts from the system of roads, lanes, stop signs, rules and lights that govern vehicles on the ground today, whether the vehicles are driven by humans or are automated. What system technologies is NASA exploring? Building on its legacy of work in air traffic management for crewed aircraft, NASA is researching prototype technologies for a UAS Traffic Management (UTM) system that could develop airspace integration requirements for enabling safe, efficient low-altitude operations. While incorporating lessons learned from the today's well-established air traffic management system, which was a response that grew out of a mid-air collision over the Grand Canyon in the early days of commercial aviation, the UTM system would enable safe and efficient low-altitude airspace operations by providing services such as airspace design, corridors, dynamic geofencing, severe weather and wind avoidance, congestion management, terrain avoidance, route planning and re-routing, separation management, sequencing and spacing, and contingency management. One of the attributes of the UTM system is that it would not require human operators to monitor every vehicle continuously. The system could provide to human managers the data to make strategic decisions related to initiation, continuation, and termination of airspace operations. This approach would ensure that only authenticated UAS could operate in the airspace. In its most mature form, the UTM system could be developed using autonomicity characteristics that include self-configuration, self-optimization and self-protection. The self-configuration aspect could determine whether the operations should continue given the current andor predicted windweather conditions. NASA envisions concepts for two types of possible UTM systems. The first type would be a Portable UTM system, which would move from between geographical areas and support operations such as precision agriculture and disaster relief. The second type of system would be a Persistent UTM system, which would support low-altitude operations and provide continuous coverage for a geographical area. Either system would require persistent communication, navigation, and surveillance (CNS) coverage to track, ensure, and monitor conformance. What is NASA doing to test the technologies? NASA's near-term goal is the development and demonstration of a possible future UTM system that could safely enable low-altitude airspace and UAS operations. Working alongside many committed government, industry and academic partners, NASA is leading the research, development and testing that is taking place in a series of activities called Technology Capability Levels (TCL), each increasing in complexity. UTM TCL1 concluded field testing in August 2015 and is undergoing additional testing at an FAA site.

UTM Low-altitude↗

DOE OSTI2023

Human‐induced salinity changes impact marine organisms and ecosystems

Abstract Climate change is fundamentally altering marine and coastal ecosystems on a global scale. While the effects of ocean warming and acidification on ecology and ecosystem functions and services are being comprehensively researched, less attention is directed toward understanding the impacts of human‐driven ocean salinity changes. The global water cycle operates through water fluxes expressed as precipitation, evaporation, and freshwater runoff from land. Changes to these in turn modulate ocean salinity and shape the marine and coastal environment by affecting ocean currents, stratification, oxygen saturation, and sea level rise. Besides the direct impact on ocean physical processes, salinity changes impact ocean biological functions with the ecophysiological consequences are being poorly understood. This is surprising as salinity changes may impact diversity, ecosystem and habitat structure loss, and community shifts including trophic cascades. Climate model future projections (of end of the century salinity changes) indicate magnitudes that lead to modification of open ocean plankton community structure and habitat suitability of coral reef communities. Such salinity changes are also capable of affecting the diversity and metabolic capacity of coastal microorganisms and impairing the photosynthetic capacity of (coastal and open ocean) phytoplankton, macroalgae, and seagrass, with downstream ramifications on global biogeochemical cycling. The scarcity of comprehensive salinity data in dynamic coastal regions warrants additional attention. Such datasets are crucial to quantify salinity‐based ecosystem function relationships and project such changes that ultimately link into carbon sequestration and freshwater as well as food availability to human populations around the globe. It is critical to integrate vigorous high‐quality salinity data with interacting key environmental parameters (e.g., temperature, nutrients, oxygen) for a comprehensive understanding of anthropogenically induced marine changes and its impact on human health and the global economy.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2021

X‐ray scattering reveals disordered linkers and dynamic interfaces in complexes and mechanisms for DNA double‐strand break repair impacting cell and cancer biology

Abstract Evolutionary selection ensures specificity and efficiency in dynamic metastable macromolecular machines that repair DNA damage without releasing toxic and mutagenic intermediates. Here we examine non‐homologous end joining (NHEJ) as the primary conserved DNA double‐strand break (DSB) repair process in human cells. NHEJ has exemplary key roles in networks determining the development, outcome of cancer treatments by DSB‐inducing agents, generation of antibody and T‐cell receptor diversity, and innate immune response for RNA viruses. We determine mechanistic insights into NHEJ structural biochemistry focusing upon advanced small angle X‐ray scattering (SAXS) results combined with X‐ray crystallography (MX) and cryo‐electron microscopy (cryo‐EM). SAXS coupled to atomic structures enables integrated structural biology for objective quantitative assessment of conformational ensembles and assemblies in solution, intra‐molecular distances, structural similarity, functional disorder, conformational switching, and flexibility. Importantly, NHEJ complexes in solution undergo larger allosteric transitions than seen in their cryo‐EM or MX structures. In the long‐range synaptic complex, X‐ray repair cross‐complementing 4 (XRCC4) plus XRCC4‐like‐factor (XLF) form a flexible bridge and linchpin for DNA ends bound to KU heterodimer (Ku70/80) and DNA‐PKcs (DNA‐dependent protein kinase catalytic subunit). Upon binding two DNA ends, auto‐phosphorylation opens DNA‐PKcs dimer licensing NHEJ via concerted conformational transformations of XLF‐XRCC4, XLF–Ku80, and LigIV BRCT –Ku70 interfaces. Integrated structures reveal multifunctional roles for disordered linkers and modular dynamic interfaces promoting DSB end processing and alignment into the short‐range complex for ligation by LigIV. Integrated findings define dynamic assemblies fundamental to designing separation‐of‐function mutants and allosteric inhibitors targeting conformational transitions in multifunctional complexes.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

mosartwmpy: A Python implementation of the MOSART-WM coupled hydrologic routing and water management model

mosartwmpy is a Python implementation of the Model for Scale Adaptive River Transport with Water Management (MOSART-WM). This new version retains the functionality of the legacy model (written in FORTRAN) while providing new features to enhance user experience and extensibility. MOSART is a large-scale river-routing model used to study riverine dynamics of water, energy, and biogeochemistry cycles across local, regional, and global scales (Li et al., 2013). The WM component introduced by Voisin et al. (2013) represents river regulation through reservoir storage and release operations, diversions from reservoir releases, and allocation to sectoral water demands. Each reservoir release is independently calibrated using long-term mean monthly inflow into the reservoir, long-term mean monthly demand associated with this reservoir, and reservoir goals (flood control, irrigation, recreation, etc.). Generic monthly pre-release rules and storage targets are set up for individual reservoirs; however, those releases are updated annually for inter-annual variability (dry or wet year) and daily for environmental constraints such as flow minimum release and minimum/maximum storage levels. The WM model allows an evaluation of the impact of water management over multiple river basins at once (global, continental scales) and with consistent representation of human operations over the full domain.

97 MATHEMATICS AND COMPUTING↗

DOE OSTI2022

Network analysis uncovers the communication structure of SARS-CoV-2 spike protein identifying sites for immunogen design

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered myriad efforts to understand the structure and dynamics of this complex pathogen. The spike glycoprotein of SARS-CoV-2 is a significant target for immunogens as it is the means by which the virus enters human cells, while simultaneously sporting mutations responsible for immune escape. These functional and escape processes are regulated by complex molecular-level interactions. Our study presents quantitative insights on domain and residue contributions to allosteric communication, immune evasion, and local- and global-level control of functions through the derivation of a weighted graph representation from all-atom MD simulations. Focusing on the ancestral form and the D614G-variant, we provide evidence of the utility of our approach by guiding the selection of a mutation that alters the spike’s stability. Taken together, the network approach serves as a valuable tool to evaluate communication “hot-spots” in proteins to guide design of stable immunogens.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin

The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa . We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.

59 BASIC BIOLOGICAL SCIENCES↗