Static all-atom energetic mappings of the SARS-Cov-2 spike protein and dynamic stability analysis of “Up” versus “Down” protomer states

The SARS-CoV-2 virion responsible for the current world-wide pandemic COVID-19 has a characteristic Spike protein (S) on its surface that embellishes both a prefusion state and fusion state. The prefusion Spike protein (S) is a large trimeric protein where each protomer may be in a so-called Up state or Down state, depending on the configuration of its receptor binding domain (RBD) within its distal, prefusion S1 domain. The Up state is believed to allow binding of the virion to ACE-2 receptors on human epithelial cells, whereas the Down state is believed to be relatively inactive or reduced in its binding behavior. We have performed detailed all-atom, dominant energy landscape mappings for noncovalent interactions (charge, partial charge, and van der Waals) of the SARS-CoV-2 Spike protein in its static prefusion state based on two recent and independent experimental structure publications. We included both interchain interactions and intrachain (domain) interactions in our mappings in order to determine any telling differences (different so-called “glue” points) between residues in the Up and Down state protomers. The S2 proximal, fusion domain demonstrated no appreciable energetic differences between Up and Down protomers, including interchain as well as each protomer’s intrachain, S1-S2 interactions. However, the S1 domain interactions across neighboring protomers, which include the RBD-NTD cross chain interactions, showed significant energetic differences between Up-Down and Down-Down neighboring protomers. This included, for example, a key RBD residue ARG357 in the Up-Down interaction and a three residue sequence ALA520-PRO521-ALA522, associated with a turn structure in the RBD of the Up state protomer, acting as a stabilizing interaction with the NTD of its neighbor protomer. Additionally, our intra chain dominant energy mappings within each protomer, identified a significant “glue” point or possible “latch” for the Down state protomer between the S1 subdomain, SD1, and the RBD domain of the same protomer that was completely missing in the Up state protomer analysis. Ironically, this dominant energetic interaction in the Down state protomer involved the backbone atoms of the same three residue sequence ALA520-PRO521-ALA522 of the RBD with the amino acid R-group of GLN564 in the SD1 domain. Thus, this same three residue sequence acts as a stabilizer of the RBD in the Up conformation through its interactions with its neighboring NTD chain and a kind of latch in the Down state conformation through its interactions with its own SD1 domain. The dominant interaction energy residues identified here are also conserved across reported variations of SARS-CoV-2, as well as the closely related virions SARS-Cov and the bat corona virus RatG13. We conducted preliminary molecular dynamics simulations across 0.1 μ seconds to see if this latch provided structural stability and indeed found that a single point mutation (Q564G) resulted in the latch releasing transforming the protomer from the Down to the Up state conformation. Full trimeric Spike protein studies of the same mutation across all protomers, however, did not exhibit latch release demonstrating the critical importance of interchain interactions across the S1 domain, including RBD-NTD neighboring chain interactions. Therapies aimed at disrupting these noncovalent interactions could be a viable route for the physico-chemical mitigation of this deadly virion.

Structural and functional insight into the Mycobacterium tuberculosis protein PrpR reveals a novel type of transcription factor

The pathogenicity of Mycobacterium tuberculosis depends upon its ability to catabolize host cholesterol. Upregulation of the methylcitrate cycle (MCC) is required to assimilate and detoxify propionyl-CoA, a cholesterol degradation product. The transcription of key genes prpC and prpD in MCC is activated by MtPrpR, a member of a family of prokaryotic transcription factors whose structures and modes of action have not been clearly defined. We show that MtPrpR has a novel overall structure and directly binds to CoA or short-chain acyl-CoA derivatives to form a homotetramer that covers the binding cavity and locks CoA tightly inside the protein. The regulation of this process involves a [4Fe4S] cluster located close to the CoA-binding cavity on a neighboring chain. Mutations in the [4Fe4S] cluster binding residues rendered MtPrpR incapable of regulating MCC gene transcription. The structure of MtPrpR without the [4Fe4S] cluster-binding region shows a conformational change that prohibits CoA binding. The stability of this cluster means it is unlikely a redox sensor but may function by sensing ambient iron levels. These results provide mechanistic insights into this family of critical transcription factors who share similar structures and regulate gene transcription using a combination of acyl-CoAs and [4Fe4S] cluster.

EFFECT OF LONG-RANGE DENSITY-DISPLACEMENT TYPE INTERACTION ON SMALL POLARON

In this work, renormalization of effective mass of an electron due to small polaron formation is studied within the framework of Extended Holstein model. It is assumed that electron moves along one-dimensional chain of ions and interacts with ions vibrations of neighboring chain via long-range density–displacement type force. By means of exact calculations, renormalized mass of nonadiabatic small polaron is obtained at strong coupling limit. Obtained results compared with those of small polaron mass of ordinary Holstein model. An effect of ions vibrations polarization on small polaron mass is addressed.

Structure and thermal behavior of the new superprotonic conductor Cs2(HSO4)(H2PO4)

Ongoing studies of the CsHSO4–CsH2PO4 system, aimed at developing novel proton conducting solids, resulted in the new compound Cs2(HSO4)(H2PO4) (dicesium hydrogensulfate dihydrogenphosphate). Single-crystal X-ray diffraction (performed at room temperature) revealed Cs2(HSO4)(H2PO4) to crystallize in space group P21/n with lattice parameters a = 7.856 (8), b = 7.732 (7), c = 7.827 (7) Å, and β = 99.92 (4)°. The compound has a unit-cell volume of 468.3 (8) Å3 and two formula units per cell, giving a calculated density of 3.261 Mg m−3. Six non-H atoms and two H atoms were located in the asymmetric unit, with SO4 and PO4 groups randomly arranged on the single tetrahedral anion site. Refinement using all observed reflections yielded weighted residuals of 0.0890 and 0.0399 based on F 2 and F values, respectively. Anisotropic temperature factors were employed for all six non-H atoms and fixed isotropic temperature factors for the two H atoms. The structure contains zigzag chains of hydrogen-bonded anion tetrahedra that extend in the [010] direction. Each tetrahedron is additionally linked to a tetrahedron in a neighboring chain to give a planar structure with hydrogen-bonded sheets lying parallel to (1¯01). Thermal analysis of the superprotonic transition in Cs2(HSO4)(H2PO4) showed that the transformation to the high-temperature phase occurs by a two-step process. The first is a sharp transition at 334 K and the second a gradual transition from 342 to 378 K. The heat of transformation for the entire process (∼330–382 K) is 44 ± 2 J g−1. Thermal decomposition of Cs2(HSO4)(H2PO4) takes place at much higher temperatures, with an onset of approximately 460 K.

Patterned Polymer Films

Polymer films that contain well-defined patterns can be used in a variety of novel applications. For example such films can serve as the scaffolding in fabricating organic/inorganic composites with controlled architectures. One means of forming patterned films is to anchor the ends of homopolymers onto a substrate (so that the ends are fixed and cannot move) and immerse the system in a poor solvent. The incompatibility between the polymer and solvent drives the system to phase-separate. Since the ends are immobilized however, the polymers can only escape the unfavorable solvent by clustering with neighboring chain s into distinct aggregates or “pinned micelles.” These micelles have a uniform size and spacing, and form a regular array on the surface. In this article, we use theoretical models to extend this concept and show that, by tethering copolymers—chains that contain more than one type of monomer—we can drive the system to form more complicated surface patterns. These copolymer patterns provide a handle for engineering the interaction between surfaces and thus facilitate the fabrication of novel optical devices. If the copolymer films are composed of both hydrophilic and hydrophobic domains, the surface can also be used as a template for growing biological cells with tailored shapes and sizes.

Ranges of shielded nuclides from thermal-neutron fission

Average ranges in Al of shielded nuclides 86Rb and 136Cs and several chain-yield species from thermal-neutron fission of 233U and 235U have been measured. The values obtained (in mg/cm2 Al) are, for 233U: 86Rb, 3.88 ± 0.04; 136CS, 2.80 ± 0.01; and for 235U: 86Rb, 3.76 ± 0.03; 136Cs, 2.81 ± 0.01. A range–energy transformation was used to determine average kinetic energies [Formula: see text] of the secondary fragments. In agreement with previous work, the shielded nuclides are found to have smaller [Formula: see text] values than neighboring chain-yield species. The deficits of [Formula: see text] are, for 233U, 4 and 8 MeV, and for 235U, 8 and 10 MeV, respectively, for 86Rb and 136Cs. Most of the range experiments were done with the thick-catcher method followed by conventional radiochemical treatment of the catcher foils. Ranges of 20 products from 233U were determined in preliminary experiments in which gross γ-ray spectra of fission products in the catcher foils were observed with a Ge(Li) detector. The kinetic-energy deficits of the shielded species are interpreted by Monte Carlo calculations of prompt-neutron emission.