Unveiling of Pyrimidindinones as Potential Anti-Norovirus Agents—A Pharmacoinformatic-Based Approach

The RNA-dependent RNA polymerase (RdRp) receptor is an attractive target for treating human norovirus (HNV). A computer-aided approach like e-pharmacophore, molecular docking, and single point energy calculations were performed on the compounds retrieved from the Development Therapeutics Program (DTP) AIDS Antiviral Screen Database to identify the antiviral agent that could target the HNV RdRp receptor. Induced-fit docking (IFD) results showed that compounds ZINC1617939, ZINC1642549, ZINC6425208, ZINC5887658 and ZINC32068149 bind with the residues in the active site-B of HNV RdRp receptor via hydrogen bonds, salt bridge, and electrostatic interactions. During the molecular dynamic simulations, compounds ZINC6425208, ZINC5887658 and ZINC32068149 displayed an unbalanced backbone conformation with HNV RdRp protein, while ZINC1617939 and ZINC1642549 maintained stability with the protein backbone when interacting with the residues. Hence, the two new concluding compounds discovered by the computational approach can be used as a chemotype to design promising antiviral agents aimed at HNV RdRp.

A Hessian free method to prevent zero-point energy leakage in classical trajectory simulation

The problem associated with the zero-point energy (ZPE) leak in classical trajectory calculations is well known. Since ZPE is a manifestation of the quantum uncertainty principle, there are no restrictions on energy during the classical propagation of nuclei. This phenomenon can lead to unphysical results, such as forming products without the ZPE in the internal vibrational degrees of freedom (DOFs). The ZPE leakage also permits reactions below the quantum threshold for the reaction. We have developed a new Hessian-free method, inspired by the Lowe-Andersen thermostat model, to prevent energy dipping below a threshold in the local-pair (LP) vibrational DOFs. The idea is to pump the leaked energy to the corresponding local vibrational mode, taken from the other vibrational DOFs. We have applied the new correction protocol on the ab initio ground-state molecular dynamics simulation of the water dimer (H20)2, which dissociates due to unphysical ZPE spilling from the high-frequency OH modes. The LP-ZPE method has been able to prevent the ZPE spilling of the OH stretching modes by pumping back the leaked energy into the corresponding modes while this energy is taken from the other modes of the dimer itself, keeping the system as a microcanonical ensemble.

Understanding Proton Transfer in Non-aqueous Biopolymers based on Helical Peptides: A Quantum Mechanical Study

Histidine (an imidazole-based amino acid) is a promising building block for short aromatic peptides containing a proton donor/acceptor moiety. Previous studies have shown that polyalanine helical peptides substituted at regular intervals with histidine residues exhibit both structural stability as well as high proton affinity and high conductivity. Here, we present first-principle calculations of non-aqueous histidine-containing 310-,  and -helices and show that they are able to form hydrogen-bonded networks mimicking proton wires that have the ability to shuttle protons via the Grotthuss shuttling mechanism. The formation of these wires enhances the stability of the helices, and our structural characterizations confirm that the secondary structures are conserved despite distortions of the backbones. In all cases, the helices exhibit high proton affinity and proton transfer barriers on the order of 1~4 kcal/mol. Zero-point energy calculations suggest that for these systems, ground state vibrational energy can provide enough energy to cross the proton transport energy barrier. Additionally, ab initio molecular dynamics results suggests that the protons are transported unidirectionally through the wire at a rate of approximately 2 Å every 20 fs. These results demonstrate that efficient deprotonation-controlled proton wires can be formed using non-aqueous histidine-containing helical peptides.

Casimir Forces Out of Thermal Equilibrium Near A Superconducting Transition

We present a comprehensive analysis of the out-of-equilibrium Casimir pressure between two high-T c superconducting plates, each kept at a different temperature. Two interaction regimes can be distinguished. While the zero-point energy dominates in the near field, thermal effects become important at large interplate separations causing a drop in the force’s magnitude compared with the usual thermal-equilibrium case. Our detailed calculations highlight the competing role played by propagating and evanescent modes. Moreover, as one of the plates undergoes the superconducting transition, we predict a sudden discontinuity in the force for any plate distance, which has not been previously observed in other systems. The sensitivity of the dielectric function of the high-T c superconductors makes them ideal systems for a possible direct measurement of the out-of-equilibrium Casimir pressure.

Nonenzymatic Deamidation Mechanism on a Glutamine Residue with a C-Terminal Adjacent Glycine Residue: A Computational Mechanistic Study

The deamidation of glutamine (Gln) residues, which occurs non-enzymatically under physiological conditions, triggers protein denaturation and aggregation. Gln residues are deamidated via the cyclic glutarimide intermediates to l-α-, d-α-, l-β-, and d-β-glutamate residues. The production of these biologically uncommon amino acid residues is implicated in the pathogenesis of autoimmune diseases. The reaction rate of Gln deamidation is influenced by the C-terminal adjacent (N +1) residue and is highest in the Gln-glycine (Gly) sequence. Here, we investigated the effect of the (N + 1) Gly on the mechanism of Gln deamidation and the activation barrier using quantum chemical calculations. Energy-minima and transition-state geometries were optimized by the B3LYP density functional theory, and MP2 calculations were used to obtain the single-point energy. The calculated activation barrier (85.4 kJ mol−1) was sufficiently low for the reactions occurring under physiological conditions. Furthermore, the hydrogen bond formation between the catalytic ion and the main chain of Gly on the C-terminal side was suggested to accelerate Gln deamidation by stabilizing the transition state.

New species of fermions and bosons, cosmological constant problem and a farewell to spin–statistics theorem

If dark matter exists in the form of ultralight fermionic and bosonic species, then (a) it can accelerate evaporation of astrophysical black holes to the extent that their lifetimes can be reduced to astronomical time scales, a and (b) if there are extremely large number of such species it has the potential to solve the hierarchy problem [H. Davoudiasl, P. B. Denton and D. A. McGady, Phys. Rev. D 103 (2021) 055014; G. Dvali, Fortschr. Phys. 58 (2010) 528]. Here, we put forward a proposal that darkness of many of these new particles is natural, and in addition, the net zero point energy of the fermions exactly cancels that coming from the new bosons. The needed fermion–boson equality, and matching the fermion–boson degrees of freedom, comes about naturally. A very direct argument that allows the departure from the spin–statistics theorem is presented.

BSE49, a diverse, high-quality benchmark dataset of separation energies of chemical bonds

We present an extensive and diverse dataset of bond separation energies associated with the homolytic cleavage of covalently bonded molecules (A-B) into their corresponding radical fragments (A. and B.). Our dataset contains two different classifications of model structures referred to as “Existing” (molecules with associated experimental data) and “Hypothetical” (molecules with no associated experimental data). In total, the dataset consists of 4502 datapoints (1969 datapoints from the Existing and 2533 datapoints from the Hypothetical classes). The dataset covers 49 unique X-Y type single bonds (except H-H, H-F, and H-Cl), where X and Y are H, B, C, N, O, F, Si, P, S, and Cl atoms. All the reference data was calculated at the (RO)CBS-QB3 level of theory. The reference bond separation energies are non-relativistic ground-state energy differences and contain no zero-point energy corrections. This new dataset of bond separation energies (BSE49) is presented as a high-quality reference dataset for assessing and developing computational chemistry methods.

Improved semiclassical model for real-time evaporation of matrix black holes

In this paper, we study real-time classical matrix mechanics of a simplified [Formula: see text] matrix model inspired by the black hole evaporation problem. This is a step towards making a quantitative model of real-time evaporation of a black hole, which is realized as a bound state of D0-branes in string theory. The model we study is the reduction of Yang–Mills in [Formula: see text] dimension to [Formula: see text] dimensions, which has been corrected with an additional potential that can be interpreted as a zero-point energy for fermions. Our goal is to understand the lifetime of such a classical bound state object in the classical regime. To do so, we pay particular attention to when [Formula: see text]-particles separate to check that the “off-diagonal modes” of the matrices become adiabatic and use that information to improve on existing models of evaporation. It turns out that the naive expectation value of the lifetime with the fermionic correction is infinite. This is a logarithmic divergence that arises from very large excursions in the separation between the branes near the threshold for classical evaporation. The adiabatic behavior lets us get some analytic control of the dynamics in this regime to get this estimate. This divergence is cutoff in the quantum theory due to quantization of the adiabatic parameter, resulting in a long lifetime of the bound state, with a parametric dependence of order [Formula: see text].

A Classical Physics Approach for Space Expansion: The Hubble Drift

Accelerating expansion of metric space AEMS is investigated with classical Newtonian mechanics. Relying on earlier positions, the results are analyzed to reveal what could be a new understanding of the theoretical framework of the subject. Notably, it is shown that space is physical; it comprises aggregated waveforms of the chemical elements and shares identical quantization, periodicity and mass-evolution with matter. Three plausible methods are identified for classical investigation of the Hubble effect, all three give same result, Ho= 49.5 km s-1Mpc. AEMS results from coupling of light’s 36.9o tangential component (vr=0.75rω) to periodic space, i.e., a component of the vacuum field’s e-m radiation couples to logarithmically decreasing distance scales, vr(E)/drE, to create an acceleration relative to space not time. Multiplicity of the Hubble constant aHo is traceable to corresponding multiplicity of universes nested within our universe. Mass ejection from a cosmic quantum envelope is the cosmic equivalence of radioactivity, it signals ageing and eventual disappearance of the host periodic envelope from visibility. Reality is an imperturbable (ideal) Steady-State, observations thought to invalidate this view are hugely misinterpreted, an explosion in or of spacetime marking the beginning of time could not conceivably sustain, over the aeons, an accelerating expansion of metric space; furthermore, the cosmic microwave background is the zero-point energy or vacuum radiation. The active galactic nucleus or black hole is not a singularity, it is a two-way valve that facilitates circulation of mass-energy matrices across the four phases or ref. frames of reality. There is no new creation of space or matter, only continuous recycling in line with NASA’s recent observation.