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DOE OSTI2017

High-Dimensional Atomistic Neural Network Potentials for Molecule–Surface Interactions: HCl Scattering from Au(111)

Ab initio molecular dynamics (AIMD) simulations of molecule–surface scattering allow first-principles characterization of the dynamics. However, the large number of density functional theory calculations along the trajectories is very costly, limiting simulations of long-time events and giving rise to poor statistics. To avoid this computational bottleneck, we report here the development of a high-dimensional molecule–surface interaction potential energy surface (PES) with movable surface atoms, using a machine learning approach. With 60 degrees of freedom, this PES allows energy transfer between the energetic impinging molecule and thermal surface atoms. Classical trajectory calculations for the scattering of DCl from Au(111) on this PES are found to agree well with AIMD simulations, with ~105-fold acceleration. Scattering of HCl from Au(111) is further investigated and compared with available experimental results.

Kolb, Brian↗

DOE OSTI2016

Novel Effects of Compressed CO 2 Molecules on Structural Ordering and Charge Transport in Conjugated Poly(3-hexylthiophene) Thin Films

We report the effects of compressed CO 2 molecules as a novel plasticization agent for poly(3- hexylthiophene) (P3HT) conjugated polymer thin films. In-situ neutron reflectivity experiment demonstrated the excess sorption of CO 2 molecules in the P3HT thin films (about 40 nm in thickness) at low pressure (P = 8.2 MPa) under the isothermal condition of T = 36 °C, which is far below the polymer bulk melting point. The results evidenced that these CO 2 molecules accelerated the crystallization process of the polymer on the basis of ex-situ grazing incidence Xray diffraction measurements after drying the films via rapid depressurization to atmospheric pressure: not only the out-of-plane lamellar ordering of the backbone chains but also intra-plane π-π stacking of the side chains were significantly improved, when compared to those in the control P3HT films subjected to conventional thermal annealing (at T = 170 °C). Electrical measurements elucidated that the CO 2 -annealed P3HT thin films exhibited enhanced charge carrier mobility along with decreased background charge carrier concentration and trap density compared to those in the thermally annealed counterpart. This is attributed to the CO 2 -induced increase in polymer chain mobility that can drive the detrapping of molecular oxygen and healing of conformational defects in the polymer thin film. Given the universality of the excess sorption of CO 2 regardless of the type of polymers, the present findings suggest that the CO 2 annealing near the critical point can be useful as a robust processing strategy for improving structural and electrical characteristics of other semiconducting conjugated polymers and related systems such as polymer: fullerene bulk heterojunction films.tion films.

36 MATERIALS SCIENCE↗

DOE OSTI2016

Mapping the Transmission Functions of Single-Molecule Junctions

Charge transport characteristics of single-molecule junctions are often governed by a transmission function that dictates the probability of electrons or holes tunneling across the junction. Here, we present a new and simple technique for measuring the transmission function of molecular junctions in the coherent tunneling limit, over an energy range of 2 eV around the Fermi energy. We create molecular junctions in an ionic environment with electrodes having different areas exposed, which results in the formation of electric double layers of dissimilar density on the two electrodes. This allows us to electrostatically shift the molecular resonance relative to the junction Fermi levels in a manner that depends on the sign of the applied bias, enabling us to map out the junction’s transmission function and determine the dominant orbital for charge transport in the molecular junction. We demonstrate this technique using two groups of molecules: one group having molecular resonance energies relatively far from EF and one group having molecular resonance energies within the accessible bias window. Our results compare well with previous electrochemical gating data and with transmission functions computed ab initio. Furthermore, with the second group of molecules, we are able to examine the behavior of a molecular junction as a resonance shifts into the bias window. This work provides a new, experimentally simple route for exploring the fundamentals of charge transport at the nanoscale.

74 ATOMIC AND MOLECULAR PHYSICS↗

DOE OSTI2019

Facile Fabrication of a Multifunctional Metal–Organic Framework-based Sensor Exhibiting Exclusive Solvochromic Behaviors toward Ketone Molecules

To probe the efficient strategy for preparing a multifunctional sensing material, the facile synthesis strategies and successful examples are urgently required. Through the utilization of a hexadentate ligand derived from cyclotriphosphazene, which displays spiral configurations and multiple connection modes, a novel metal–organic framework (MOF) was constructed via one-step synthesis from low-cost raw materials. The presence of multiple interaction sites decorating the helical channels of the reported MOF gives rise to exclusive solvochromic-sensing behavior for small ketone molecules such as acetone, acetophenone, and 2,5-diketohexane. Additionally, the helical structure of a manganese-carboxylate chain allows for the pore volume not only be available for the adsorption of large organic molecules but also enables the enantiopure selective separation of 1-phenylethanol (ee 35.99 %). Furthermore, the structural analysis of the acetophenone-encapsulated sample allowed the solvochromic mechanism to be elucidated, which should be ascribed to the strong hydrogen-bonding interaction between the guest molecules and specific sites on a host matrix. The experimental results have not only clearly manifested the vital role of starting materials of MOFs, including the connection modes and spatial configuration, but also have provided very valuable insight for the future assembly of novel multifunctional sensing materials.

36 MATERIALS SCIENCE↗

DOE OSTI2019

Kinetic Isolation between Turnovers on Au 18 Nanoclusters: Formic Acid Decomposition One Molecule at a Time

Formic acid (HCOOH or FA) is a clean, safe, and renewable hydrogen storage material. Although Au catalysts decompose vapor-phase FA with high activity and selectivity toward hydrogen, the active site and reaction mechanism remain unclear. Here, we show that the subnanometric Au 18 cluster (0.8 nm in diameter) is likely the active species for FA decomposition. We performed coverage self-consistent, density functional theory-based kinetic Monte Carlo simulations of FA decomposition on gas-phase Au18 clusters, predicting 100% selectivity toward hydrogen and turnover frequencies close to experimentally determined values. The active site is made up of a triangular ensemble of three atoms each possessing a coordination number of 5. Although there are two active site ensembles on the Au18 cluster, their occupations are strongly correlated because of strong, stabilizing interactions between pairs of open-shell adsorbates mediated by the superatomic nature of the cluster. Because the occupation of the active sites blocks the dissociation of additional HCOOH molecules, there is kinetic isolation between turnovers: only one HCOOH molecule can dissociate on the cluster at a time. This explains the extraordinary, experimentally observed selectivity of Au catalysts toward HD during decomposition of HCOOD and DCOOH. Our work offers nanoscale insights into the reaction mechanisms of FA decomposition over Au. This represents a rare example of heterogeneous catalysis by a cluster that catalyzes reactants one molecule at a time. Our work on Au18 thus sheds light on how the unique electronic properties of subnanometric clusters can be used to design quasi-molecular catalysts with high activity and selectivity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2017

Hierarchical Self-Organization of AB n Dendron-like Molecules into a Supramolecular Lattice Sequence

To understand the hierarchical self-organization behaviors of soft materials as well as their dependence on molecular geometry, a series of ABn dendron-type giant molecules based on polyhedral oligomeric silsesquioxane (POSS) nanoparticles were designed and synthesized. The apex of these molecules is a hydrophilic POSS cage with fourteen hydroxyl groups (denoted DPOSS). At its periphery, there are different numbers (n = 1–8) of hydrophobic POSS cages with seven isobutyl groups (denoted BPOSS), connected to the apical DPOSS via flexible dendron type linker(s). With varying the BPOSS number from one to seven, a supramolecular lattice formation sequence ranging from lamella (DPOSS-BPOSS), double gyroid (space group of Ia3d, DPOSS-BPOSS2), hexagonal cylinder (space group of P6mm, DPOSS-BPOSS3), Frank-Kasper A15 (space group of Pm3n, DPOSS-BPOSS4, DPOSS-BPOSS5, and DPOSS-BPOSS6), to Frank-Kasper sigma (space group of P42/mnm, DPOSS-BPOSS7) phases can be observed. The nanostructure formations in this series of ABn dendron-type giant molecules are mainly directed by the macromolecular geometric shapes. Furthermore, within each spherical motif, the soft spherical core is consisted of hydrophilic DPOSS cages with flexible linkages, while the hydrophobic BPOSS cages form the relative rigid shell and contact with neighbors to provide decreased interfaces among the spherical motifs for constructing final polyhedral motifs in these Frank-Kasper lattices. This study provides the design principle of macromolecules with specific geometric shapes and functional groups to achieve anticipated structures and macroscopic properties.

Feng, Xueyan↗

DOE OSTI2016

Spatial Distributions of Guest Molecule and Hydration Level in Dendrimer-Based Guest–Host Complex

Using the electrostatic complex of G4 poly(amidoamine) (PAMAM) dendrimer with an amphiphilic surfactant as a model system, contrast variation small angle neutron scattering (SANS) is implemented to resolve the key structural characteristics of dendrimer-based guest–host system. Quantifications of the radial distributions of the scattering length density and the hydration level within the complex molecule reveal that the surfactant is embedded in the peripheral region of dendrimer and the steric crowding in this region increases the backfolding of the dendritic segments, thereby reducing the hydration level throughout the complex molecule. Here, the insights into the spatial location of the guest molecules as well as the perturbations of dendrimer conformation and hydration level deduced here are crucial for the delicate design of dendrimer-based guest–host system for biomedical applications.

36 MATERIALS SCIENCE↗

DOE OSTI2016

Topological analysis of void space in phosphate frameworks: Assessing storage properties for the environmentally important guest molecules and ions: CO 2 , H 2 O, UO 2 , PuO 2 , U, Pu, Sr 2+ , Cs + , CH 4 , and H 2

The entrapment of environmentally important materials to enable containment of polluting wastes from industry or energy production, storage of alternative fuels, or water sanitation, is of vital and immediate importance. Many of these materials are small molecules or ions that can be encapsulated via their adsorption into framework structures to create a host-guest complex. This is an ever-growing field of study and, as such, the search for more suitable porous materials for environmental applications is fundamental to progress. However, many industrial areas that require the use of adsorbents are fraught with practical challenges such as high temperatures, rapid gas expansion, radioactivity, or repetitive gas cycling, that the host material must withstand. Inorganic phosphates have a proven history of rigid structures, thermal stability, and are suspected to possess good resistance to radiation over geologic time scales. Furthermore, various experimental studies have established their ability to adsorb small molecules, such as water. In light of this, all known crystal structures of phosphate frameworks with meta- (P 3 O 9 ) or ultra- (P 5 O 14 ) stoichiometries are combined in a data-mining survey together with all theoretically possible structures of Ln a P b O c (where a, b, c are any integer, and Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, or Tm) that are statistically likely to form. Topological patterns within these framework structures are used to assess their suitability for hosting a variety of small guest molecules or ions that are important for environmental applications: CO 2 , H 2 O, UO 2 , PuO 2 , U, Pu, Sr 2+ , Cs + , CH 4 and H 2 . A range of viable phosphate-based host-guest complexes are identified from this data-mining and pattern-based structural analysis. Moreover, distinct topological preferences for hosting such guests are found, and metaphosphate stoichiometries are generally preferred over ultraphosphate configurations.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2018

Anion Exchange Membrane Electrolyzers as Alternative for Upgrading of Biomass-Derived Molecules

Upgrading biomass derived platform molecules to fuels or chemicals provides a unique alternative for the substitution of fossil sources with renewables. Electrochemical reduction (ECR) is one of the upgrading technologies, alternative to catalytic reduction, which only requires electricity as the energy input, which can be derived from carbon free energy sources. Moreover, ECR does not require external addition of hydrogen, as this can be generated in-situ. In this work an anion exchange membrane (AEM) electrolyte assembly (MEA) has been tested for the efficient reduction of biomass derived molecules, and compared with a cation exchange membrane (CEM) MEA. The cathode electrocatalyst has been modified with the addition of hydrophobicity and anion exchange ionomers, and incorporated onto an anion exchange membrane. Electrochemical experiments were performed with a metal free electrocatalyst in the presence and absence of surrogate compounds. The results showed that changes in the catalyst formulation can increase the overpotential for the competing hydrogen evolution reaction (HER), while significantly enhancing the reduction of the organic molecules. Bulk electrolysis experiments demonstrated higher efficiencies for furfural ECR in an AEM-MEA vs. AEM-CEM, reaching conversions up to 94% at 50 mA cm 2 and in the absence of supporting electrolyte. Moreover, AEM-MEA was able to facilitate water management during the reduction process and contribute to the separation of small carboxylic acids.

09 BIOMASS FUELS↗

DOE OSTI2024

Coercive Fields Exceeding 30 T in the Mixed-Valence Single-Molecule Magnet (Cp iPr5 ) 2 Ho 2 I 3

Mixed-valence dilanthanide complexes of the type (Cp iPr5 ) 2 Ln 2 I 3 (Cp iPr5 = pentaisopropylcyclopentadienyl; Ln = Gd, Tb, Dy) featuring a direct Ln–Ln σ-bonding interaction have been shown to exhibit well-isolated high-spin ground states and, in the case of the Tb and Dy variants, a strong axial magnetic anisotropy that gives rise to a large magnetic coercivity. Here, we report the synthesis and characterization of two new mixed-valence dilanthanide compounds in this series, (Cp iPr5 ) 2 Ln 2 I 3 (1-Ln; Ln = Ho, Er). Both compounds feature a Ln–Ln bonding interaction, the first such interaction in any molecular compounds of Ho or Er. Like the Tb and Dy congeners, both complexes exhibit high-spin ground states arising from strong spin–spin coupling between the lanthanide 4f electrons and a single σ-type lanthanide–lanthanide bonding electron. Beyond these similarities, however, the magnetic properties of the two compounds diverge. In particular, 1-Er does not exhibit observable magnetic blocking or slow magnetic relaxation, while 1-Ho exhibits magnetic blocking below 28 K, which is the highest temperature among Ho-based single-molecule magnets, and a spin reversal barrier of 556(4) cm –1 . Additionally, variable-field magnetization data collected for 1-Ho reveal a coercive field of greater than 32 T below 8 K, more than 6-fold higher than observed for the bulk magnets SmCo 5 and Nd 2 Fe 14 B, and the highest coercive field reported to date for any single-molecule magnet or molecule-based magnetic material. Multiconfigurational calculations, supported by far-infrared magnetospectroscopy data, reveal that the stark differences in magnetic properties of 1-Ho and 1-Er arise from differences in the local magnetic anisotropy of the lanthanide centers.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2017

“Roller-Wheel”-Type Pt-Containing Small Molecules and the Impact of “Rollers” on Material Crystallinity, Electronic Properties, and Solar Cell Performance

We report the synthesis, characterization, and detailed comparison of a series of novel Pt-bisacetylide containing conjugated small molecules possessing an unconventional “roller-wheel” shaped structure that is distinctly different from the “dumbbell” designs in traditional Pt-bisacetylide containing conjugated polymers and small molecules. The relationships between the chemical nature and length of the “rollers” and the electronic and physical properties of the materials are carefully studied by steady-state spectroscopy, cyclic voltammetry, differential scanning calorimetry, single-crystal X-ray diffraction, transient absorption spectroscopy, theoretical calculation, and device application. It was revealed that if the roller are long enough, these molecules can “slip-stack” in the solid state, leading to high crystallinity and charge mobility. Organic solar cells were fabricated and showed power conversion efficiencies up to 5.9%, out-performing all existing Pt-containing materials. The device performance was also found to be sensitive to optimization conditions and blend morphologies, which are a result of the intricate interplay among materials crystallinity, phase separation, and the relative positions of the lowest singlet and triplet excited states.

36 MATERIALS SCIENCE↗

DOE OSTI2011

Pyrolysis of Phenethyl Phenyl Ether Tethered in Mesoporous Silica. Effects of Confinement and Surface Spacer Molecules on Product Selectivity

There has been expanding interest in exploring porous metal oxides as a confining environment for organic molecules resulting in altered chemical and physical properties including chemical transformations. In this paper, we examine the pyrolysis behavior of phenethyl phenyl ether (PPE) confined in mesoporous silica by covalent tethers to the pore walls as a function of tether density and the presence of co-tethered surface spacer molecules of varying structure (biphenyl, naphthyl, octyl, and hexadecyl). The PPE pyrolysis product selectivity, which is determined by two competitive free-radical pathways cycling through the two aliphatic radical intermediates (PhCH CH2OPh and PhCH2CH OPh), is shown to be dramatically different from that measured in the liquid phase as well as for PPE tethered to the exterior surface of nonporous silica nanoparticles. Tailoring the pore surface with spacer molecules further alters the selectivity such that the PPE reaction channel involving a molecular rearrangement (O-C phenyl shift in PhCH2CH OPh), which accounts for 25 % of the products in the liquid phase, can be virtually eliminated under pore confinement conditions. The origin of this change in selectivity is discussed in the context of steric constraints on the rearrangement path, confinement effects, pore surface curvature, and hydrogen bonding of PPE with residual surface silanols supplemented by nitrogen physisorption data and molecular dynamics simulations.

Kidder, Michelle↗

DOE OSTI2011

On the Electronic Structures and Electron Affinities of the m- Benzoquinone (BQ) Diradical and the o-, p- BQ Molecules. A Synergetic Photoelectron Spectroscopic and Theoretical Study

Electron affinities (EAs) and electronic structures of benzoquinone molecules (BQs) play a vital role in a wide range of applications involving these molecules from biological photosynthesis to energy conversion processes. In this article, we report a systematic spectroscopic probe on the electronic structures and EAs of all three isomers (o-, m-, and p- BQs) employing photodetachment photoelectron spectroscopy (PES) and ab initio electronic structure calculations. PES spectra of three radical anions (BQ •- ) were taken with different photon energies and at low temperature in order to accurately determine the EAs and probe ground as well as the excited states of the corresponding neutral molecules. Similar spectral pattern was observed in the o- and p- BQ •- spectra, each revealing a broad ground state feature and a large band gap, followed by well-resolved excited states peaks. The EAs of o- and p- BQ are determined to be 1.90, 1.85 eV, and singlet-triplet band gaps to be 1.68, and 2.32 eV, respectively. In contrast, the spectrum of m- BQ •- is distinctly different from its two congeners, with no clear band gap and a much higher EA (2.89 eV). Accompanying theoretical calculations confirm experimental EAs and band gaps, and further unravel a triplet ground state for m-BQ in contrast to singlet ground states for o- and p- isomers. The diradical nature of m-BQ, consistent with its non-Kekulé structure, is primarily responsible for the observed high EA and also explains its nonexistence in bulk materials.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

DOE OSTI2011

Structural Effects and Interactions of Carbon Dioxide Molecules Adsorbed on Ni, Zn, and Cd Nitroprussides

A thorough structural characterization of the synthesized Ni-, Zn-, and Cd-nitroprussides (NPs) with X-ray diffraction (XRD), thermogravimetric analysis, diffuse reflectance infrared Fourier transform spectrometry (DRIFTS), M€ossbauer spectroscopy, and magnetic measurements was performed. We studied the innovative part of the research for the structural effects and the interactions of the CO 2 molecule with the Ni-, Zn-, Cd-NP frameworks. DRIFTS of adsorbed molecules, high pressure adsorption, and in situ XRD adsorption experiments were performed. The DRIFTS spectra displayed peaks assigned to CO 2 physical adsorption and the formation of adducts (M 2+ ∙∙∙ O=C=O). The fitting of the adsorption data to the Dubinin₋Radushkevich equation and a Langmuir-type equation for volume filling allowed the calculation of the micropore volume and the isosteric heats of adsorption. Furthermore, the calculated parameters indicated an unusual behavior of the adsorption process in Cd-NP at high pressure. This fact was caused by the interaction of CO 2 molecules with the framework cations and the small adsorption space of Cd-NP. The Ni- and Zn-NPs behaved normally. The Pawley fitting of the XRD profiles of the dehydrated materials and under CO 2 adsorption indicated that in both cases Ni-NP, Zn-NP, and Cd-NPs displayed the Fm$\overline{3}$m, R$\overline{3}$, and Pnma space groups, respectively. The dehydrated samples demonstrated a change in the cell parameters. But, only Cd-NP presented a noticeable variation of its cell parameters under CO 2 adsorption. This fact was linked to the unusual behavior of the adsorption process in Cd-NP. In addition, we show that dehydrated Ni-, Zn-, and Cd-NPs can store 27, 22, and 15 wt % of CO 2 at 298 K and 9 atm., respectively. Then, Ni- and Cd-NPs are excellent for CO 2 storage, and Cd-NP is good for gas cleaning.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2013

Density Functional Theory Study of the Complexation of the Uranyl Dication with Anionic Phosphate Ligands with and without Water Molecules

The structures, vibrational frequencies and energetics of anhydrous and hydrated complexes of UO2 2+ with the phosphate anions H2PO4 -, HPO4 2-, and PO4 3- were predicted at the density functional theory (DFT) and MP2 molecular orbital theory levels as isolated gas phase species and in aqueous solution by using self-consistent reaction field (SCRF) calculations with different solvation models. The geometries and vibrational frequencies of the major binding modes for these complexes are compared to experiment where possible and good agreement is found. The uranyl moiety is nonlinear in many of the complexes, and the coordination number (CN) 5 in the equatorial plane is the predominant binding motif. The phosphates are found to bind in both monodentate and bidentate binding modes depending on the charge and the number of water molecules. The SCRF calculations were done with a variety of approaches, and different SCRF approaches were found to be optimal for different reaction types. The acidities of HxPO4 3-x in HxPO4 3-x(H2O)4, x = 0-3 complexes were calculated with different SCRF models and compared to experiment. Phosphate anions can displace water molecules from the first solvation shell at the uranyl exothermically. The addition of water molecules can cause the bonding of H2PO4 - and HPO4 2- to change from bidentate to monodentate exothermically while maintaining CN 5. The addition of water can generate monodentate structures capable of cross-linking to other uranyl phosphates to form the types of structures found in the solid state. [UO2(HPO4)(H2O)3] is predicted to be a strong base in the gas phase and in aqueous solution. It is predicted to be a much weaker acid than H3PO4 in the gas phase and in solution.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2017

Mechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate

The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition. This inhibitory role of the PR domain limits Grb2-independent recruitment of SOS to the membrane through binding of Ras·GTP in the SOS allosteric binding site. More generally, this assay strategy enables characterization of the functional behaviour of GEFs with single-molecule precision but without the need for purification.

Science & Technology - Other Topics↗

DOE OSTI2023

An autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering

The recruitment of 53BP1 to chromatin, mediated by its recognition of histone H4 dimethylated at lysine 20 (H4K20me2), is important for DNA double-strand break repair. Using a series of small molecule antagonists, we demonstrate a conformational equilibrium between an open and a pre-existing lowly populated closed state of 53BP1 in which the H4K20me2 binding surface is buried at the interface between two interacting 53BP1 molecules. In cells, these antagonists inhibit the chromatin recruitment of wild type 53BP1, but do not affect 53BP1 variants unable to access the closed conformation despite preservation of the H4K20me2 binding site. Thus, this inhibition operates by shifting the conformational equilibrium toward the closed state. Our work therefore identifies an auto-associated form of 53BP1—autoinhibited for chromatin binding—that can be stabilized by small molecule ligands encapsulated between two 53BP1 protomers. Such ligands are valuable research tools to study the function of 53BP1 and have the potential to facilitate the development of new drugs for cancer therapy.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Small molecule BLVRB redox inhibitor promotes megakaryocytopoiesis and stress thrombopoiesis in vivo

Biliverdin IXβ reductase (BLVRB) is an NADPH-dependent enzyme previously implicated in a redox-regulated mechanism of thrombopoiesis distinct from the thrombopoietin (TPO)/c-MPL axis. Here, we apply computational modeling to inform molecule design, followed by de novo syntheses and screening of unique small molecules retaining the capacity for selective BLVRB inhibition as a novel platelet-enhancing strategy. Two distinct classes of molecules are identified, and NMR spectroscopy and co-crystallization studies confirm binding modes within the BLVRB active site and ring stacking between the nicotinamide moiety of the NADP+ cofactor. A diazabicyclo derivative displaying minimal off-target promiscuity and excellent bioavailability characteristics promotes megakaryocyte speciation in biphenotypic (erythro/megakaryocyte) cellular models and synergizes with TPO-dependent megakaryocyte formation in hematopoietic stem cells. Upon oral delivery into mice, this inhibitor expands platelet recovery in stress thrombopoietic models with no adverse effects. In this work, we identify and validate a cellular redox inhibitor retaining the potential to selectively promote megakaryocytopoiesis and enhance stress-associated platelet formation in vivo distinct from TPO receptor agonists.

36 MATERIALS SCIENCE↗