Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “Active target”

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.

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

At least 919 records · Page 51
All sourcesNASA NTRSDOE OSTI
NASA NTRS1994

Exobiology site priorities for Mars Pathfinder

The fact that life developed on the Earth within the first billion years of its history makes it quite plausible that life may have also developed on Mars. If life did develop on Mars, it undoubtedly left behind a fossil record. Such a fossil record is likely to be more accessible than either subsurface environments that may harbor life, or scattered 'oases' that may be present at the surface. Consequently, the post-Viking approach of Mars exobiology has shifted focus to search for evidence of an ancient martian biosphere. This has led to the emergence of a new subdiscipline of paleontology, herein termed 'exopaleontology', which deals with the exploration for fossils on other planets and whose core concepts derive from Earth-based Precambrian paleontology, microbial ecology, and sedimentology. Potential targets on Mars for subaqueous spring deposits, sedimentary cements, and evaporites are ancient terminal lake basins where hydrological systems could have endured for some time under arid conditions. Potential targets for the Mars Pathfinder mission include channeled impact craters and areas of deranged drainage associated with outflows in northwest Arabia and Xanthe Terra, where water may have ponded temporarily to form lakes. The major uncertainty of such targets is their comparatively younger age and the potentially short duration of hydrological activity compared to older paleolake basins found in the southern hemisphere. However, it has been suggested that cycles of catastrophic flooding associated with Tharsis volcanism may have sustained a large body of water, Oceanus Borealis, in the northern plains area until quite late in martian history. Although problematic, the shoreline areas of the proposed northern ocean provide potential targets for a Mars Pathfinder mission aimed at exploring for carbonates or other potentially fossiliferous marine deposits. Carbonates and evaporites possess characteristic spectra signatures in the near-infrared and should be detectable using rover-based spectroscopy and other methods for in situ mineralogical analysis.

Farmer, Jack D.↗
DOE OSTI2022

An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4

Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. Finally, by identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Heterologous expression of a fully active Azotobacter vinelandii nitrogenase Fe protein in Escherichia coli

ABSTRACT The functional versatility of the Fe protein, the reductase component of nitrogenase, makes it an appealing target for heterologous expression, which could facilitate future biotechnological adaptations of nitrogenase-based production of valuable chemical commodities. Yet, the heterologous synthesis of a fully active Fe protein of Azotobacter vinelandii ( Av NifH) in Escherichia coli has proven to be a challenging task. Here, we report the successful synthesis of a fully active Av NifH protein upon co-expression of this protein with Av IscS/U and Av NifM in E. coli . Our metal, activity, electron paramagnetic resonance, and X-ray absorption spectroscopy/extended X-ray absorption fine structure (EXAFS) data demonstrate that the heterologously expressed Av NifH protein has a high [Fe 4 S 4 ] cluster content and is fully functional in nitrogenase catalysis and assembly. Moreover, our phylogenetic analyses and structural predictions suggest that Av NifM could serve as a chaperone and assist the maturation of a cluster-replete Av NifH protein. Given the crucial importance of the Fe protein for the functionality of nitrogenase, this work establishes an effective framework for developing a heterologous expression system of the complete, two-component nitrogenase system; additionally, it provides a useful tool for further exploring the intricate biosynthetic mechanism of this structurally unique and functionally important metalloenzyme. IMPORTANCE The heterologous expression of a fully active Azotobacter vinelandii Fe protein (AvNifH) has never been accomplished. Given the functional importance of this protein in nitrogenase catalysis and assembly, the successful expression of AvNifH in Escherichia coli as reported herein supplies a key element for the further development of heterologous expression systems that explore the catalytic versatility of the Fe protein, either on its own or as a key component of nitrogenase, for nitrogenase-based biotechnological applications in the future. Moreover, the “clean” genetic background of the heterologous expression host allows for an unambiguous assessment of the effect of certain nif-encoded protein factors, such as AvNifM described in this work, in the maturation of AvNifH, highlighting the utility of this heterologous expression system in further advancing our understanding of the complex biosynthetic mechanism of nitrogenase.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Minimally disruptive optical control of protein tyrosine phosphatase 1B

Protein tyrosine phosphatases regulate a myriad of essential subcellular signaling events, yet they remain difficult to study in their native biophysical context. Here we develop a minimally disruptive optical approach to control protein tyrosine phosphatase 1B (PTP1B)—an important regulator of receptor tyrosine kinases and a therapeutic target for the treatment of diabetes, obesity, and cancer—and we use that approach to probe the intracellular function of this enzyme. Our conservative architecture for photocontrol, which consists of a protein-based light switch fused to an allosteric regulatory element, preserves the native structure, activity, and subcellular localization of PTP1B, affords changes in activity that match those elicited by post-translational modifications inside the cell, and permits experimental analyses of the molecular basis of optical modulation. Findings indicate, most strikingly, that small changes in the activity of PTP1B can cause large shifts in the phosphorylation states of its regulatory targets.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2010

Active Debris Removal - A Grand Engineering Challenge for the Twenty-First Century

The collision between Iridium 33 and Cosmos 2251 in 2009 underlined the potential of an ongoing collision cascade effect (the Kessler Syndrome ) in the near-Earth orbital debris environment. A 2006 NASA analysis of the instability of the debris population in the low Earth orbit (LEO, the region below 2000 km altitude) shows that the environment has reached a point where the debris population will continue to increase in the next 200 years, even without any future launches. The increase is driven by fragments generated via collisions among existing objects in LEO. In reality, the situation will be worse than this prediction because satellite launches will continue and unexpected major breakups may continue to occur. Mitigation measures commonly adopted by the international space community (such as the 25-year rule) will help, but will be insufficient to stop the population growth. To better preserve the near-Earth space environment for future generations, active debris removal (ADR) should be considered. The idea of active debris removal is not new. However, due to the monumental technical, resource, operational, legal, and political challenges associated with removing objects from orbit, it has not yet been widely considered feasible. The recent major breakup events and the environment modeling efforts have certainly reignited the interest in using active debris removal to remediate the environment. This trend is further highlighted by the National Space Policy of the United States of America, released by the White House in June 2010, where the President explicitly directs NASA and the Department of Defense to pursue research and development of technology and techniques, to mitigate and remove on-orbit debris, reduce hazards, and increase understanding of the current and future debris environment. A 2009 modeling study by the NASA Orbital Debris Program Office has shown that, in order to maintain the LEO debris population at a constant level for the next 200 years, an active debris removal of about five objects per year is needed. The targets identified for removal are those with the highest mass and collision probability products. Analyses from the study indicate that the majority of those objects are spent upper stages with masses ranging from 1 to more than 8 metric tons, residing in several altitude regions and concentrated in about 10 inclination bands. To remove five of those objects per year in a cost-effective manner truly represents a grand challenge in engineering and technology development. An end-to-end debris removal operation includes, in general terms, launches orbit rendezvous, precision tracking, stabilization (of the tumbling motion), capture, and deorbit of the targets. An ADR system deigned to remove a single object is not very cost-effective. Therefore, the repeatability of the removal system is almost a requirement. Some of the technologies involved in the ADR process do exist, but the difficulty is to make them more cost effective. Other technologies, such as ways to stabilize a massive tumbling upper stage and the capture mechanisms, are new and will require major innovative research and development efforts. This paper summarizes an updated assessment of the environment, including what needs to be done to control the population growth, and outlines the major engineering and technology challenges to carry out active debris removal to preserve the environment.

Liou, Jer-Chyi↗
DOE OSTI2022

Peak Prediction Using Multi Layer Perceptron (MLP) for Edge Computing ASICs Targeting Scientific Applications

High data rate detectors play an integral part in scientific research and their development is actively pursued at High Energy Physics (HEP) facilities around the world. Edge Machine Learning (ML) offers the ability to reduce data rates by integrating ML algorithms into Application Specific Integrated Circuits (ASICs) on the front end electronics. In this work, we explore a set of neural network architectures for predicting the peak amplitudes in the detector's sensor response. We have designed and synthesized several MLP based neural networks comparing their inference accuracy, power consumption, and area targeting for minimal latency. The neural networks are synthesized in a commercial 65nm process. The effect of quantizing the network's weights and biases on hardware performance and area is reported. We also conduct design space exploration to compare between design alternatives

47 OTHER INSTRUMENTATION↗
DOE OSTI2021

Wavelength Dependence of Activity-induced Photometric Variations for Young Cool Stars in Hyades

We investigate photometric variations due to stellar activity that induce systematic radial-velocity errors (so-called “jitter”) for the four targets in the Hyades open cluster observed by the K2 mission (EPIC 210721261, EPIC 210923016, EPIC 247122957, and EPIC 247783757). Applying Gaussian process regressions to the K2 light curves and the near-infrared (NIR) light curves observed with the IRSF 1.4 m telescope, we derive the wavelength dependences of the photometric signals due to stellar activity. To estimate the temporal variations in the photometric variability amplitudes between the two observation periods of K2 and IRSF, separated by more than 2 yr, we analyze a number of K2 targets in Hyades that have also been observed in Campaigns 4 and 13 and find a representative variation rate over 2 yr of 38% ± 71%. Taking this temporal variation into account, we constrain projected sizes and temperature contrast properties of the starspots in the stellar photosphere to be approximately 10% and 0.95%, respectively. These starspot properties can induce relatively large differences in the variability amplitude over different observational passbands, and we find that radial-velocity jitter may be more suppressed in the NIR than previously expected. Our result supports profits of ongoing exoplanet search projects that are attempting to detect or confirm young planets in open clusters via radial-velocity measurements in the NIR.

47 OTHER INSTRUMENTATION↗
DOE OSTI2020

Durability test of a flowing-water target for isotope harvesting

A high intensity proton irradiation was performed with the flowing-water isotope harvesting target at the University of Wisconsin-Madison Cyclotron Laboratory to measure the rate of degradation of the target shell during irradiation conditions. The beam reached an intensity of 34 µA by the end of the irradiation and covered an area of 0.7 cm 2 on the target. Radiolysis products, such as H 2 O 2 , H 2 , and O 2 , were measured in the bulk water of the system and found to be present at much lower levels than predicted by literature escape yields. Radionuclides formed in the target shell were measured in the system water as a radiotracer for target degradation. Using a simple, beam intensity dependent model, a corrosion rate of 1.5E-6 μm/(μA*s) was found to match the measured radiotracer activities at various points in the irradiation. Furthermore, this rate was used to extrapolate the lifetime of future isotope harvesting targets at the NSCL and FRIB, using the areal power density of different ion beams to scale the corrosion rate.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2020

Direct matter disassembly via electron beam control: electron-beam-mediated catalytic etching of graphene by nanoparticles

Here, we report electron-beam activated motion of a catalytic nanoparticle along a graphene step edge and associated etching of the edge. The catalytic hydrogenation process was observed to be activated by a combination of elevated temperature and electron beam irradiation. Reduction of beam fluence on the particle was sufficient to stop the process, leading to the ability to switch on and off the etching. Such an approach enables the targeting of individual nanoparticles to induce motion and beam-controlled etching of matter through activated electrocatalytic processes. The applications of electron-beam control as a paradigm for molecular-scale robotics are discussed.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2021

Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors

Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately needed. Studies targeting the SARS-CoV-2 3CL protease, which is critical for viral replication, with different peptidomimetics and warheads is an active area of research for development of potential drugs. To date, however, only a few publications have evaluated the nitrile warhead as a viral 3CL protease inhibitor, with only modest activity reported. This article describes our investigation of P3 4-methoxyindole peptidomimetic analogs with select P1 and P2 groups with a nitrile warhead that are potent inhibitors of SARS-CoV-2 3CL protease and demonstrate in vitro SARS-CoV-2 antiviral activity. A selectivity for SARS-CoV-2 3CL protease over human cathepsins B, S and L was also observed with the nitrile warhead, which was superior to that with the aldehyde warhead. A co-crystal structure with SARS-CoV-2 3CL protease and a reversibility study indicate that a reversible, thioimidate adduct is formed when the catalytic sulfur forms a covalent bond with the carbon of the nitrile. Furthermore, this effort also identified efflux as a property limiting antiviral activity of these compounds, and together with the positive attributes described these results provide insight for further drug development of novel nitrile peptidomimetics targeting SARS-CoV-2 3CL protease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

US Department of Energy Better Plants Program’s Approach to Manufacturing Workforce Development

Multiple studies suggest that by 2030, millions of jobs may go unfilled because of a significant skills gap between the current manufacturing workforce and the workforce needed to support the shift toward advanced and sustainable manufacturing. According to US manufacturers, finding the right talent is more difficult now than in previous years. Developing a well-trained workforce will play a critical role in transforming the manufacturing sector into a net-zero contributor of greenhouse gas emissions by 2050. To help reduce energy, water, waste, and greenhouse gas emissions as well as build a strong, sustainable manufacturing workforce, the US Department of Energy created the voluntary Better Plants program in 2011. This study discusses the program’s various workforce development activities, including in-plant trainings, virtual in-plant trainings, and in-person bootcamps. The target audiences, training objectives, and topics designed to upskill workers for a low-carbon manufacturing future are described. Feedback that was collected (e.g., new training topics, certifications, hands-on activities) while working with more than 270 US manufacturers for the past 12 years on workforce development are discussed. Finally, some strategies are proposed to address the feedback.

Guo, Wei↗
DOE OSTI2023

Pyridine-containing substrate analogs are restricted from accessing the human cytochrome P450 8B1 active site by tryptophan 281

The human oxysterol 12α-hydroxylase cytochrome P450 8B1 (CYP8B1) is a validated drug target for both type 2 diabetes and nonalcoholic fatty liver disease, but effective selective inhibitors are not yet available. Herein, steroidal substrate-mimicking compounds with a pyridine ring appended to the C12 site of metabolism were designed as inhibitors, synthesized, and evaluated in terms of their functional and structural interactions with CYP8B1. While the pyridine nitrogen was intended to coordinate the CYP8B1 active site heme iron, none of these compounds elicited shifts in the CYP8B1 Soret absorbance consistent with this type of interaction. However, when CYP8B1 was cocrystallized with the pyridine-containing compound with the 3-keto-Δ4 steroid backbone most similar to the endogenous substrate, it was apparent that this ligand was bound in a channel leading to the active site, instead of near the heme iron. Inspection of this structure suggested that tryptophan 281 directly above the heme might restrict active site binding of potential inhibitors with this design. This hypothesis was supported when a CYP8B1 W281F mutation did allow all three compounds to coordinate the heme iron as designed. These results indicated that the design of next-generation CYP8B1 inhibitors should be compatible with the low-ceiling tryptophan immediately above the heme iron.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Final Report: Preparation and Evaluation of N-Type CdSeTe and CdTe as an Absorber in Thin Film PV

The primary objective of this project was to demonstrate n-type CdTe and CdSeTe films prepared by in-situ doping methods using pre-doped source material. Our goal was to achieve electron density (>10 17 cm -3 ) and lifetime (>10 ns) in n-type CdTe and CdSeTe films. The focus was on indium as the dopant, as it is suitable for incorporation during melt growth of CdTe. It was thought that indium doped bulk crystals might exhibit self compensation and high resistivity, so post-growth annealing studies were planned to manipulate crystal stoichiometry, defects and electrical activity. Single crystals of CdTe:In and CdSe 0.4 Te 0.6 :In, with target In concentration 10 19 cm -3 , were grown by the vertical Bridgman crystal growth method at Washington State University (WSU). Incorporation of the intended In into the crystals was ~25%-30%, (2.5-3) ×10 18 cm -3 , according to glow discharge mass spectrometry (GDMS). Carrier concentration in CdTe:In crystals were very low until after a Cd anneal, at which point the concentration reached 8 ×10 17 cm -3 (~27% activation) according to Hall effect and time resolved photoluminescence (TRPL). CdSeTe:In, on the other hand, had ~100% carrier activation with no post-growth treatments, resulting in ~3×10 18 cm -3 carriers with a lifetime of 1.5 ns, near the radiative limit for this material.

14 SOLAR ENERGY↗
DOE OSTI2025

Trusted Simulation: Considering Model Quality in the Context of User Trust

A high‐quality simulation model should help its users to easily and appropriately calibrate their trust in the model. Traditional evaluation metrics such as validation and robustness are necessary but insufficient for this task. Trust calibration depends on factors like the model's transparency, applicability to intended use, usability, reputation, and consideration of potential bias. This article proposes a framework for designing and evaluating system dynamics models by considering factors that contribute to the proper calibration of user trust. This framework takes inspiration from trusted artificial intelligence, broadening our traditional concept of model quality and explicitly focusing on what users need to consider a model trustworthy and to understand the model's relevance to its intended purpose. The trusted simulation framework can improve our integration of model quality activities throughout the modeling process, leading to more impactful and better‐targeted model design, development, and evaluation.

Naugle, Asmeret Bier [Sandia National Laboratories↗
DOE OSTI2025

Synthetic microbial communities: Bridging research and application in second-generation bioenergy feedstock microbiomes

The sustainable production of purpose-grown bioenergy feedstocks is essential in transitioning away from fossil fuels. Synthetic communities (SynComs) are consortia of microorganisms that can be used as biological interventions to support objectives like plant growth and stress tolerance. This review examines the state of knowledge regarding microbiomes and SynComs of second-generation bioenergy feedstocks, focusing on the rhizosphere. We first provide an overview of second-generation feedstocks, including switchgrass (Panicum virgatum), miscanthus (Miscanthus × giganteus), sorghum (Sorghum spp.), sugarcane (Saccharum spp.), and poplar (Populus spp.), and summarize our current understanding of their plant-soil-microbiome ecology. We next discuss considerations in the objectives, design, and evaluation of SynComs to enhance feedstock production, and then critically review the literature around their use. Our literature analysis revealed that SynCom performance varied substantially between controlled pilot experiments and field trials, possibly due to system complexity that could not be fully considered in their design and pilot evaluation. We identified a gap in the use of SynComs to support the unique sustainability objectives of biofuel feedstock agriculture, presenting an opportunity to leverage these additional microbial traits in SynCom designs. Finally, we emphasize the importance of targeted research to identify the ecological principles that govern the assembly, activation, and persistence of microbes in the feedstock rhizosphere, thereby enhancing our capacity to manage microbiomes under diverse environmental conditions and ensure their functionality. Beyond biofuels, SynComs are a promising microbiome management strategy for crop production; however, an ecologically informed design and evaluation of SynComs are advised.

SynCom↗
DOE OSTI2020

Tailoring a Three-Phase Microenvironment for High-Performance Oxygen Reduction Reaction in Proton Exchange Membrane Fuel Cells

Despite tremendous progress in catalyst development for rate-limiting cathodic oxygen reduction reaction (ORR), reducing Pt usage while meeting performance requirements in practical proton exchange membrane fuel cells (PEMFCs) remains a challenge. The ORR in PEMFCs occurs at a catalyst–electrolyte–gas three-phase interface. A desirable interface should exhibit highly active and available catalytic sites, as well as allow efficient oxygen and proton feeding to the catalytic sites and timely removal of water to avoid interface flooding. In this work, we report the design of a three-phase microenvironment in PEFMCs, showing that carbon surface chemistry can be tuned to modulate its interaction with the ionomers and create favorable transport paths for rapid delivery of both reactants and products. With such an elaborate interfacial design, for the first time we have demonstrated PEMFCs with all key ORR catalyst performance metrics, including mass activity, rated power, and durability, surpassing the US Department of Energy targets.

25 ENERGY STORAGE↗
DOE OSTI2021

Silencing of RSPO1 mitigates obesity-related renal fibrosis in mice by deactivating Wnt/β-catenin pathway

Highlights: • Renal RSPO1 expression was increased in mice fed on high-fat diet for 12 weeks. • Silencing RSPO1 remitted kidney dysfunction and renal fibrosis in obesity mice. • Silencing RSPO1 inhibited LGR4 expression and Wnt/β-catenin pathway activation. • RSPO1/LGR4 axis was involved in obesity-related renal fibrosis. Obesity, a global epidemic, is one of the critical causes of chronic kidney disease (CKD). R-spondin1 (RSPO1) possessing the potential to activate Wnt/β-catenin pathway was reported to be elevated in circulation of obesity objects. However, the function of RSPO1 and the latent mechanism in obesity-related CKD are still left to be revealed. In the present study, renal RSPO1 expression was increased in mice fed on high-fat diet (HFD) for 12 weeks. Lentivirus-mediated RSPO1 knockdown partly recovered obesity-related metabolic symptoms, while distinctly remitted kidney dysfunction and renal fibrosis in obesity mice. In vitro, recombinant RSPO1 was found to elevate leucine-rich repeat-containing G protein coupled receptor 4 (LGR4) expression, promote Wnt/β-catenin signaling pathway activation, facilitate epithelial-mesenchymal transition (EMT) and increase collagen deposition in HK2 renal tubular cells. Such pro-fibrotic effect of RSPO1 was diminished by LGR4 siRNA in HK2 cells. In summary, we demonstrate that RSPO1/LGR4 axis is involved in obesity-related renal fibrosis at least through activating Wnt/β-catenin signaling pathway, providing a potential therapeutic target for this disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease

Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle coronavirus disease 2019 (COVID-19). SARS-CoV-2 main protease (Mpro) is an established drug target for the design of protease inhibitors. We performed a structure–activity relationship (SAR) study of noncovalent compounds that bind in the enzyme’s substrate-binding subsites S1 and S2, revealing structural, electronic, and electrostatic determinants of these sites. The study was guided by the X-ray/neutron structure of Mpro complexed with Mcule-5948770040 (compound 1), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of 1. In vitro enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on Mpro inhibition, showing that (1) maintaining correct geometry of an inhibitor’s P1 group is essential to preserve the hydrogen bond with the protonated His163; (2) a positively charged linker is preferred; and (3) subsite S2 prefers nonbulky modestly electronegative groups.

60 APPLIED LIFE SCIENCES↗