G-Quadruplexes as Sensors of Intracellular Na+/K+ Ratio: Potential Role in Regulation of Transcription and Translation.

Data on the structure of G-quadruplexes, noncanonical nucleic acid forms, supporting an idea of their potential participation in regulation of gene expression in response to the change in intracellular Na+i/K+i ratio are considered in the review. Structural variety of G-quadruplexes, role of monovalent cations in formation of this structure, and thermodynamic stability of G-quadruplexes are described. Data on the methods of their identification in the cells and biological functions of these structures are presented. Analysis of information about specific interactions of G-quadruplexes with some proteins was conducted, and their potential participation in the development of some pathological conditions, in particular, cancer and neurodegenerative diseases, is considered. Special attention is given to the plausible role of G-quadruplexes as sensors of intracellular Na+i/K+i ratio, because alteration of this parameter affects folding of G-quadruplexes changing their stability and, thereby, organization of the regulatory elements of nucleic acids. The data presented in the conclusion section demonstrate significant change in the expression of some early response genes under certain physiological conditions of cells and tissues depending on the intracellular Na+i/K+i ratio.

Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus.

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.

Modeling Spin-Crossover Dynamics.

In this article, we review nonadiabatic molecular dynamics (NAMD) methods for modeling spin-crossover transitions. First, we discuss different representations of electronic states employed in the grid-based and direct NAMD simulations. The nature of interstate couplings in different representations is highlighted, with the main focus on nonadiabatic and spin-orbit couplings. Second, we describe three NAMD methods that have been used to simulate spin-crossover dynamics, including trajectory surface hopping, ab initio multiple spawning, and multiconfiguration time-dependent Hartree. Some aspects of employing different electronic structure methods to obtain information about potential energy surfaces and interstate couplings for NAMD simulations are also discussed. Third, representative applications of NAMD to spin crossovers in molecular systems of different sizes and complexities are highlighted. Finally, we pose several fundamental questions related to spin-dependent processes. These questions should be possible to address with future methodological developments in NAMD.

Increased Extracellular Sodium Concentration as a Factor Regulating Gene Expression in Endothelium.

Hyperosmotic stimulation of endothelial cells often leads to its dysfunction accompanied, among other things, by proinflammatory response. The mechanisms of this phenomenon are not fully understood. It may arise due to increase in the plasma Na+ concentration, due to increase in the extracellular osmolarity, increase in the intracellular Na+i/K+i ratio, and/or change in the cell stiffness. In the present study we investigated the effects of short-term increase in osmolarity of extracellular medium on the mRNA content of some genes important for endothelial function (including Na+i/K+i-sensitive ones) and the equivalent elasticity constant of human umbilical vein endothelial cells membranes. Hyperosmotic stimulation of these cells with NaCl but not mannitol resulted in accumulation of Na+ ions inside the cells despite the Na,K-ATPase activation, and was also accompanied by the decrease in their equivalent elasticity constant. The amount of IL1α mRNA decreased with increasing osmolarity of the extracellular medium, whereas the amount of ATF3, PAR2, and PTGS2 mRNAs increased only in response to the increasing NaCl concentration. At the same time, under the conditions of our experiments, we did not detect changes in the expression of the osmoprotective transcription factor NFAT5. The obtained data indicate that the increase of extracellular Na+ concentration in the physiological range is an independent factor that affects intracellular Na+i/K+i ratio and regulates expression of some genes (in particular, ATF3, PAR2, PTGS2) in endothelial cells.

Ab initio molecular dynamics on quantum computers.

Ab initio molecular dynamics (AIMD) is a valuable technique for studying molecules and materials at finite temperatures where the nuclei evolve on potential energy surfaces obtained from accurate electronic structure calculations. In this work, we present an approach to running AIMD simulations on noisy intermediate-scale quantum (NISQ)-era quantum computers. The electronic energies are calculated on a quantum computer using the variational quantum eigensolver (VQE) method. Algorithms for computation of analytical gradients entirely on a quantum computer require quantum fault-tolerant hardware, which is beyond NISQ-era. Therefore, we compute the energy gradients numerically using finite differences, the Hellmann-Feynman theorem, and a correlated sampling technique. This method only requires additional classical calculations of electron integrals for each degree of freedom without any additional computations on a quantum computer beyond the initial VQE run. As a proof of concept, AIMD simulations are demonstrated for the H2 molecule on IBM quantum devices. In addition, we demonstrate the validity of the method for larger molecules using full configuration interaction wave functions. As quantum hardware and noise mitigation techniques continue to improve, the method can be utilized for studying larger molecular systems.

Synaptic input as a directional cue for migrating interneuron precursors.

During CNS development, interneuron precursors have to migrate extensively before they integrate in specific microcircuits. Known regulators of neuronal motility include classical neurotransmitters, yet the mechanisms that assure interneuron dispersal and interneuron/projection neuron matching during histogenesis remain largely elusive. We combined time-lapse video microscopy and electrophysiological analysis of the nascent cerebellum of transgenic Pax2-EGFP mice to address this issue. We found that cerebellar interneuronal precursors regularly show spontaneous postsynaptic currents, indicative of synaptic innervation, well before settling in the molecular layer. In keeping with the sensitivity of these cells to neurotransmitters, ablation of synaptic communication by blocking vesicular release in acute slices of developing cerebella slows migration. Significantly, abrogation of exocytosis primarily impedes the directional persistence of migratory interneuronal precursors. These results establish an unprecedented function of the early synaptic innervation of migrating neuronal precursors and demonstrate a role for synapses in the regulation of migration and pathfinding.

A discontinuous basis enables numerically exact solution of the Schrödinger equation around conical intersections in the adiabatic representation.

Solving the vibrational Schrödinger equation in the neighborhood of conical intersections in the adiabatic representation is a challenge. At the intersection point, first- and second-derivative nonadiabatic coupling matrix elements become singular, with the singularity in the second-derivative coupling (diagonal Born-Oppenheimer correction) being non-integrable. These singularities result from discontinuities in the vibronic functions associated with the individual adiabatic states, and our group has recently argued that these divergent matrix elements cancel when discontinuous adiabatic vibronic functions sum to a continuous total nonadiabatic wave function. Here we describe the realization of this concept: a novel scheme for the numerically exact solution of the Schrödinger equation in the adiabatic representation. Our approach is based on a basis containing functions that are discontinuous at the intersection point. We demonstrate that the individual adiabatic nuclear wave functions are themselves discontinuous at the intersection point. This proves that discontinuous basis functions are essential to any tractable method that solves the Schrödinger equation around conical intersections in the adiabatic representation with high numerical precision. We establish that our method provides numerically exact results by comparison to reference calculations performed in the diabatic representation. In addition, we quantify the energetic error associated with constraining the density to be zero at the intersection point, a natural approximation. Prospects for extending the present treatment of a two-dimensional model to systems of higher dimensionality are discussed.

Predicting Intersystem Crossing Rates with AIMS-DFT Molecular Dynamics.

Accurate prediction of the intersystem crossing rates is important for many different applications in chemistry, physics, and biology. Recently, we implemented the ab initio multiple spawning (AIMS) molecular dynamics method to describe the intersystem crossing processes, where nonradiative transitions between electronic states with different spin multiplicities are mediated by spin-orbit coupling. Our original implementation of the direct AIMS dynamics used the complete active space self-consistent field (CASSCF) method to describe multiple coupled electronic states on which multidimensional Gaussian wave packets were propagated. In this work, we improve the computational efficiency and versatility of the AIMS dynamics by interfacing it with the density functional theory (DFT). The new AIMS-DFT and the earlier AIMS-CASSCF implementations are used to investigate the effects of electronic structure methods on the predicted intersystem crossing rate constants and the lowest triplet state lifetime in the GeH2 molecule. We also compare the rates and lifetimes obtained from the AIMS simulations with those predicted by the statistical nonadiabatic transition state theory (NA-TST). In NA-TST, the probabilities of spin transitions are calculated using the Landau-Zener, weak coupling, and Zhu-Nakamura formulas. Convergence of the AIMS rate constants with respect to the simulation time and the number of initial trajectories (Gaussian wave packets) is analyzed. An excellent agreement between AIMS-DFT and AIMS-CASSCF can be explained by cancelation of two effects: higher energy barriers and a stronger spin-orbit coupling in DFT relative to CASSCF. The rate constants obtained with the AIMS-DFT dynamics are about a factor of 2 larger than those predicted by the statistical NA-TST. This is likely due to the importance of the nonlocal interstate transitions missing from the NA-TST description.

Ab initio calculations of spectroscopic constants and vibrational state lifetimes of diatomic alkali-alkaline-earth cations.

We investigate the lifetimes of vibrational states of diatomic alkali-alkaline-earth cations to determine their suitability for ultracold experiments where long decoherence time and controllability by an external electric field are desirable. The potential energy and permanent dipole moment curves for the ground electronic states of LiBe+, LiMg+, NaBe+, and NaMg+ are obtained using the coupled cluster with singles doubles and triples and multireference configuration interaction methods in combination with large all-electron cc-pCVQZ and aug-cc-pCV5Z basis sets. The energies and wave functions of all vibrational states are obtained by solving the Schrödinger equation for nuclei with the B-spline basis set method. To predict the lifetimes of vibrational states, the transition dipole moments, as well as the Einstein coefficients describing spontaneous emission, and the stimulated absorption and emission induced by black body radiation are calculated. Surprisingly, in all studied ions, the lifetimes of the highest excited vibrational states are similar to the lifetimes of the ground vibrational states indicating that highly vibrationally excited ions could be useful for the ultracold experiments requiring long decoherence time.

Ab Initio Multiple Spawning Method for Intersystem Crossing Dynamics: Spin-Forbidden Transitions between (3)B1 and (1)A1 States of GeH2.

Dynamics at intersystem crossings are fundamental to many processes in chemistry, physics, and biology. The ab initio multiple spawning (AIMS) method was originally developed to describe internal conversion dynamics at conical intersections where derivative coupling is responsible for nonadiabatic transitions between electronic states with the same spin multiplicity. Here, the applicability of the AIMS method is extended to intersystem crossing dynamics in which transitions between electronic states with different spin multiplicities are mediated by relativistic spin-orbit coupling. In the direct AIMS dynamics, the nuclear wave function is expanded in the basis of frozen multidimensional Gaussians propagating on the coupled electronic potential energy surfaces calculated on the fly. The AIMS method for intersystem crossing is used to describe the nonadiabatic transitions between the (3)B1 and (1)A1 states of GeH2. The potential energies and gradients were obtained at the CASSCF(6,6)/6-31G(d) level of theory. The spin-orbit coupling matrix elements were calculated with the configuration interaction method using the two-electron Breit-Pauli Hamiltonian. The excited (3)B1 state lifetime and intersystem crossing rate constants were estimated by fitting the AIMS state population with the first-order kinetics equation for a reversible unimolecular reaction. The obtained rate constants are compared with the values predicted by the statistical nonadiabatic transition state theory with transition probabilities calculated using the Landau-Zener and weak coupling formulas.

Accurate potential energy, dipole moment curves, and lifetimes of vibrational states of heteronuclear alkali dimers.

We calculate the potential energy curves, the permanent dipole moment curves, and the lifetimes of the ground and excited vibrational states of the heteronuclear alkali dimers XY (X, Y = Li, Na, K, Rb, Cs) in the X(1)Σ(+) electronic state using the coupled cluster with singles doubles and triples method. All-electron quadruple-ζ basis sets with additional core functions are used for Li and Na, and small-core relativistic effective core potentials with quadruple-ζ quality basis sets are used for K, Rb, and Cs. The inclusion of the coupled cluster non-perturbative triple excitations is shown to be crucial for obtaining the accurate potential energy curves. A large one-electron basis set with additional core functions is needed for the accurate prediction of permanent dipole moments. The dissociation energies are overestimated by only 14 cm(-1) for LiNa and by no more than 114 cm(-1) for the other molecules. The discrepancies between the experimental and calculated harmonic vibrational frequencies are less than 1.7 cm(-1), and the discrepancies for the anharmonic correction are less than 0.1 cm(-1). We show that correlation between atomic electronegativity differences and permanent dipole moment of heteronuclear alkali dimers is not perfect. To obtain the vibrational energies and wave functions the vibrational Schrödinger equation is solved with the B-spline basis set method. The transition dipole moments between all vibrational states, the Einstein coefficients, and the lifetimes of the vibrational states are calculated. We analyze the decay rates of the vibrational states in terms of spontaneous emission, and stimulated emission and absorption induced by black body radiation. In all studied heteronuclear alkali dimers the ground vibrational states have much longer lifetimes than any excited states.

PySpawn: Software for Nonadiabatic Quantum Molecular Dynamics.

The ab initio multiple spawning (AIMS) method enables nonadiabatic quantum molecular dynamics simulations in an arbitrary number of dimensions, with potential energy surfaces provided by electronic structure calculations performed on-the-fly. However, the intricacy of the AIMS algorithm complicates software development, deployment on modern shared computer resources, and postsimulation data analysis. PySpawn is a nonadiabatic molecular dynamics software package that addresses these issues. The program is designed to be easily interfaced with electronic structure software, and an interface to the TeraChem software package is described here. PySpawn introduces a task-based reorganization of the AIMS algorithm, allowing fine-grained restart capability and setting the stage for efficient parallelization in a future release. PySpawn includes a user-friendly and interactive Python analysis module that will enable novice users to painlessly adopt AIMS. As a demonstration of PySpawn's simulation capability and analysis module, we report complete active space self-consistent field-based AIMS simulations of the 1,2-dithienyl-1,2-dicyanoethene molecule, a promising molecular photoswitch.

Nonadiabatic Quantum Molecular Dynamics in Dense Manifolds of Electronic States.

Most nonadiabatic molecular dynamics methods require the determination of a basis of adiabatic or diabatic electronic states at every time step, but in dense manifolds of electronic states, such approaches become intractable. A notable exception is Ehrenfest molecular dynamics, which can be implemented without explicit determination of such a basis but suffers from unphysical behavior when propagation on a mean-field potential energy surface (PES) does not accurately reflect the true dynamics on multiple electronic states. Here we introduce the multiple cloning for dense manifolds of states (MCDMS) method, a systematically improvable approximation to the multiple cloning method. MCDMS avoids both the mean-field PES problem and the need to compute the full electronic spectrum. This is achieved by reformulating multiple cloning to use a subspace of approximate eigenstates constructed from the time-dependent Ehrenfest electronic wave function. By application to model systems, we show that this approach allows a substantial reduction in the size of the required electronic basis without significant loss in accuracy.