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15 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Materials Data on BH3 by Materials Project

BH3 crystallizes in the monoclinic P2_1/c space group. The structure is zero-dimensional and consists of two borane molecules. B3- is bonded to four H1+ atoms to form edge-sharing BH4 tetrahedra. There are a spread of B–H bond distances ranging from 1.19–1.32 Å. There are three inequivalent H1+ sites. In the first H1+ site, H1+ is bonded in a single-bond geometry to one B3- atom. In the second H1+ site, H1+ is bonded in a single-bond geometry to one B3- atom. In the third H1+ site, H1+ is bonded in an L-shaped geometry to two equivalent B3- atoms.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Materials Data on Mg(BH3)2 by Materials Project

Mg(BH3)2 crystallizes in the triclinic P1 space group. The structure is three-dimensional. there are four inequivalent Mg2+ sites. In the first Mg2+ site, Mg2+ is bonded in a 5-coordinate geometry to seven H+0.67+ atoms. There are a spread of Mg–H bond distances ranging from 2.00–2.30 Å. In the second Mg2+ site, Mg2+ is bonded in a 6-coordinate geometry to six H+0.67+ atoms. There are a spread of Mg–H bond distances ranging from 1.95–2.17 Å. In the third Mg2+ site, Mg2+ is bonded in a 6-coordinate geometry to six H+0.67+ atoms. There are a spread of Mg–H bond distances ranging from 1.98–2.04 Å. In the fourth Mg2+ site, Mg2+ is bonded in a 6-coordinate geometry to six H+0.67+ atoms. There are a spread of Mg–H bond distances ranging from 2.00–2.08 Å. There are eight inequivalent B3- sites. In the first B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. There are a spread of B–H bond distances ranging from 1.22–1.25 Å. In the second B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. There is one shorter (1.23 Å) and two longer (1.24 Å) B–H bond length. In the third B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. There are a spread of B–H bond distances ranging from 1.22–1.25 Å. In the fourth B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. There are a spread of B–H bond distances ranging from 1.23–1.25 Å. In the fifth B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. There are a spread of B–H bond distances ranging from 1.23–1.25 Å. In the sixth B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. There are a spread of B–H bond distances ranging from 1.22–1.25 Å. In the seventh B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. All B–H bond lengths are 1.24 Å. In the eighth B3- site, B3- is bonded in a distorted trigonal non-coplanar geometry to three H+0.67+ atoms. There are a spread of B–H bond distances ranging from 1.22–1.25 Å. There are twenty-four inequivalent H+0.67+ sites. In the first H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the second H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the third H+0.67+ site, H+0.67+ is bonded in a distorted L-shaped geometry to one Mg2+ and one B3- atom. In the fourth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the fifth H+0.67+ site, H+0.67+ is bonded in a 2-coordinate geometry to two Mg2+ and one B3- atom. In the sixth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the seventh H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the eighth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the ninth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the tenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the eleventh H+0.67+ site, H+0.67+ is bonded in a distorted L-shaped geometry to one Mg2+ and one B3- atom. In the twelfth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the thirteenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the fourteenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the fifteenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the sixteenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the seventeenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the eighteenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the nineteenth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the twentieth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the twenty-first H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the twenty-second H+0.67+ site, H+0.67+ is bonded in a distorted single-bond geometry to one Mg2+ and one B3- atom. In the twenty-third H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom. In the twenty-fourth H+0.67+ site, H+0.67+ is bonded in an L-shaped geometry to one Mg2+ and one B3- atom.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain

Viral BCL2 proteins (vBCL2s) help to sustain chronic infection of host proteins to inhibit apoptosis and autophagy. However, details of conformational changes in vBCL2s that enable binding to BH3Ds remain unknown. Using all-atom, multiple microsecond-long molecular dynamic simulations (totaling 17 μs) of the murine γ-herpesvirus 68 vBCL2 (M11), and statistical inference techniques, we show that regions of M11 transiently unfold and refold upon binding of the BH3D. Further, we show that this partial unfolding/refolding within M11 is mediated by a network of hydrophobic interactions, which includes residues that are 10 Å away from the BH3D binding cleft. We experimentally validate the role of these hydrophobic interactions by quantifying the impact of mutating these residues on binding to the Beclin1/BECN1 BH3D, demonstrating that these mutations adversely affect both protein stability and binding. To our knowledge, this is the first study detailing the binding-associated conformational changes and presence of long-range interactions within vBCL2s.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1994

On the Interaction of CO and NH3 with BH3 and BF3

BH3CO, BF3CO, BH3NH3, and BF3NH3 have been studied using density functional theory (DFT). The computed geometries are in reasonable agreement with experiment. BF3CO is found to be weakly bound. The binding energies of BH3CO, BH3NH3 , and BF3NH3 have also been computed using the coupled cluster singles and doubles level of theory, including a perturbational estimate of the connected triples [CCSD(T)]. These CCSD(T) calculations are performed using correlation consistent polarized-valence triple-zeta basis sets. These are expected to be the most accurate binding energies to date. The DFT binding energies are in good agreement with those obtained at the CCSD(T) level. The bonding is analyzed using the constrained space orbital variation (CSOV) technique. In addition to analyzing the bonding in BH3CO, BH3NH3, and BF3NH3, the CSOV approach is used to study why the bonding in BF3CO is so weak.

Bauschlicher, Charles W., Jr.↗
DOE OSTI2022

Structural basis of BAK activation in mitochondrial apoptosis initiation

BCL-2 proteins regulate mitochondrial poration in apoptosis initiation. How the pore-forming BCL-2 Effector BAK is activated remains incompletely understood mechanistically. Here we investigate autoactivation and direct activation by BH3-only proteins, which cooperate to lower BAK threshold in membrane poration and apoptosis initiation. We define in trans BAK autoactivation as the asymmetric “BH3-in-groove” triggering of dormant BAK by active BAK. BAK autoactivation is mechanistically similar to direct activation. The structure of autoactivated BAK BH3-BAK complex reveals the conformational changes leading to helix α1 destabilization, which is a hallmark of BAK activation. Helix α1 is destabilized and restabilized in structures of BAK engaged by rationally designed, high-affinity activating and inactivating BID-like BH3 ligands, respectively. Altogether our data support the long-standing hit-and-run mechanism of BAK activation by transient binding of BH3-only proteins, demonstrating that BH3-induced structural changes are more important in BAK activation than BH3 ligand affinity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Structures of the ApoL1 and ApoL2 N-terminal domains reveal a non-classical four-helix bundle motif

Apolipoprotein L1 (ApoL1) is a circulating innate immunity protein protecting against trypanosome infection. However, two ApoL1 coding variants are associated with a highly increased risk of chronic kidney disease. Here we present X-ray and NMR structures of the N-terminal domain (NTD) of ApoL1 and of its closest relative ApoL2. In both proteins, four of the five NTD helices form a four-helix core structure which is different from the classical four-helix bundle and from the pore-forming domain of colicin A. The reactivity with a conformation-specific antibody and structural models predict that this four-helix motif is also present in the NTDs of ApoL3 and ApoL4, suggesting related functions within the small ApoL family. The long helix 5 of ApoL1 is conformationally flexible and contains the BH3-like region. This BH3-like α-helix resembles true BH3 domains only in sequence and structure but not in function, since it does not bind to the pro-survival members of the Bcl-2 family, suggesting a Bcl-2-independent role in cytotoxicity. These findings should expedite a more comprehensive structural and functional understanding of the ApoL immune protein family.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing

Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness.

Silva, João P. N. (ORCID:0000000344554286)↗
DOE OSTI2020

Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering

The BCL-2 family is composed of anti- and pro-apoptotic members that respectively protect or disrupt mitochondrial integrity. Anti-apoptotic overexpression can promote oncogenesis by trapping the BCL-2 homology 3 (BH3) “killer domains” of pro-apoptotic proteins in a surface groove, blocking apoptosis. Groove inhibitors, such as the relatively large BCL-2 drug venetoclax (868 Da), have emerged as cancer therapies. BFL-1 remains an undrugged oncogenic protein and can cause venetoclax resistance. Having identified a unique C55 residue in the BFL-1 groove, we performed a disulfide tethering screen to determine if C55 reactivity could enable smaller molecules to block BFL-1's BH3-binding functionality. We found that a disulfide-bearing N-acetyltryptophan analog (304 Da adduct) effectively targeted BFL-1 C55 and reversed BFL-1-mediated suppression of mitochondrial apoptosis. Structural analyses implicated the conserved leucine-binding pocket of BFL-1 as the interaction site, resulting in conformational remodeling. Thus, therapeutic targeting of BFL-1 may be achievable through the design of small, cysteine-reactive drugs.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1992

Accurate ab initio quartic force fields for borane and BeH2

The quartic force fields of BH3 and BeH2 have been computed ab initio using an augmented coupled cluster (CCSD(T)) method and basis sets of spdf and spdfg quality. For BH3, the computed spectroscopic constants are in very good agreement with recent experimental data, and definitively confirm misassignments in some older work, in agreement with recent ab initio studies. Using the computed spectroscopic constants, the rovibrational partition function for both molecules has been constructed using a modified direct numerical summation algorithm, and JANAF-style thermochemical tables are presented.

Martin, J. M. L.↗
DOE OSTI2026

Kinetic and modeling studies of the mechanism of the dehydrogenation of Mg(BH 4 ) 2 to Mg(B 3 H 8 ) 2

Since its discovery over 15 years ago, the reversible dehydrogenation of Mg(BH 4 ) 2 to Mg(B 3 H 8 ) 2 has remained one of the more intriguing hydrogen-cycling systems. While the mechanism of this reaction has been the subject of a good deal of speculation and computational studies, prior to this work it had not been probed through kinetic studies. Previous reports of the dehydrogenation of Mg(BH 4 ) 2 to Mg(B 3 H 8 ) 2 have not included kinetic studies. The present studies have shown that the dehydrogenation of Mg(BH 4 ) 2 to Mg(B 3 H 8 ) 2 is suppressed by hydrogen pressure indicating that the rate-limiting step in this process involves hydrogen elimination. Computational modeling of kinetic data obtained from monitoring the hydrogen elimination from Mg(BH 4 ) 2 to Mg(B 3 H 8 ) 2 under static vacuum over a range of temperatures supports that the dehydrogenation occurs through a reversible three-step process in which the elimination of hydrogen from the [B 3 H 10 ] − intermediate is rate limiting. A mechanism involving the low energy transfer of neighboring BH3 groups is proposed to account for the formation of [B 3 H 8 ] − at relatively low temperatures.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Computational design of potent and selective binders of BAK and BAX

Potent and selective binders of the key proapoptotic proteins BAK and BAX have not been described. We use computational protein design to generate high affinity binders of BAK and BAX with greater than 100-fold specificity for their target. Both binders activate their targets when at low concentration, driving pore formation, but inhibit membrane permeabilization when in excess. Crystallography shows that the BAK binder induces BAK unfolding, exposing the α6 helix and BH3 domain. Together, these data suggest that upon binding, BAK or BAX unfold; at high binder concentrations, self-association of the partially folded BAK or BAX proteins is blocked and the membrane remains intact, whereas at low concentrations, dimers form, and the membrane ruptures. Our designed binders modulate apoptosis via direct, specific interactions with BAK and BAX and reveal that for therapeutic strategies targeting BAK and BAX, inhibition requires saturating binder concentrations at the site of action.

Berger, Stephanie↗
NASA NTRS1973

Chemical reactivity of hydrogen, nitrogen, and oxygen atoms at temperatures below 100 k

The synthesis of unusual compounds by techniques employing cryogenic cooling to retard their very extreme reactivity was investigated. Examples of such species that were studied are diimide (N2H2), cyclobutadiene (C4H4), cyclopropanone (C3H4O), oxirene (C2H2O), and many others. Special purpose cryogenically cooled inlet arrangements were designed such that the analyses incurred no warm-up of the cold, and frequently explosively unstable, compounds. Controlled energy electron impact techniques were used to measure critical potentials and to develop the molecular energetics and thermodynamics of these molecules and to gain some insight into their kinetic characteristics as well. Three and four carbon strained ring molecules were studied. Several reactions of oxygen and hydrogen atoms with simple molecules of H, N, C, and O in hard quench configurations were studied. And the quench stabilization of BH3 was explored as a model system in cryochemistry.

Mcgee, H. A., Jr.↗
NASA NTRS1995

Variational Calculations of Ro-Vibrational Energy Levels and Transition Intensities for Tetratomic Molecules

A description is given of an algorithm for computing ro-vibrational energy levels for tetratomic molecules. The expressions required for evaluating transition intensities are also given. The variational principle is used to determine the energy levels and the kinetic energy operator is simple and evaluated exactly. The computational procedure is split up into the determination of one dimensional radial basis functions, the computation of a contracted rotational-bending basis, followed by a final variational step coupling all degrees of freedom. An angular basis is proposed whereby the rotational-bending contraction takes place in three steps. Angular matrix elements of the potential are evaluated by expansion in terms of a suitable basis and the angular integrals are given in a factorized form which simplifies their evaluation. The basis functions in the final variational step have the full permutation symmetries of the identical particles. Sample results are given for HCCH and BH3.

Schwenke, David W.↗
DOE OSTI2023

Peptides from human BNIP5 and PXT1 and non-native binders of pro-apoptotic BAK can directly activate or inhibit BAK-mediated membrane permeabilization

Apoptosis is important for development and tissue homeostasis, and its dysregulation can lead to diseases, including cancer. As an apoptotic effector, BAK undergoes conformational changes that promote mitochondrial outer membrane disruption, leading to cell death. This is termed “activation” and can be induced by peptides from the human proteins BID, BIM, and PUMA. To identify additional peptides that can regulate BAK, we used computational protein design, yeast surface display screening, and structure-based energy scoring to identify 10 diverse new binders. We discovered peptides from the human proteins BNIP5 and PXT1 and three non-native peptides that activate BAK in liposome assays and induce cytochrome c release from mitochondria. Crystal structures and binding studies reveal a high degree of similarity among peptide activators and inhibitors, ruling out a simple function-determining property. Our results shed light on the vast peptide sequence space that can regulate BAK function and will guide the design of BAK-modulating tools and therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗