This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design.

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SummaryGlutamate transporters remove the excitatory neurotransmitter glutamate from the extracellular space after neurotransmission is complete, by taking glutamate up into neurons and glia cells. As thermodynamic machines, these transporters can also run in reverse, releasing glutamate into the extracellular space. Because glutamate is excitotoxic, this transporter-mediated release is detrimental to the health of neurons and axons, and it, thus, contributes to the brain damage that typically follows a stroke. This review highlights current ideas about the molecular mechanisms underlying glutamate uptake and glutamate reverse transport. It also discusses the implications of transporter-mediated glutamate release for cellular function under physiological and patho-physiological conditions.2008 IUBMB IUBMB Life, 60(9): 609-619, 2008

Glutamate transporters are thought to be assembled as trimers of identical subunits that line a central hole, possibly the permeation pathway for anions. Here, we have tested the effect of multimerization on transporter function. To do so, we coexpressed EAAC1 WT with the mutant transporter EAAC1 R446Q , which transports glutamine, but not glutamate. Application of 50 μM glutamate or 50 μM glutamine to cells coexpressing similar numbers of both transporters resulted in anion currents of 165 pA and 130 pA, respectively. Application of both substrates at the same time generated an anion current of 297 pA, demonstrating that the currents catalyzed by the wild-type and mutant transporter subunits are purely additive. This result is unexpected for anion permeation through a central pore, but could be explained by anion permeation through independently-functioning subunits. To further test the subunit independence, we coexpressed EAAC1 WT and EAAC1 H295K , a transporter with a 90-fold reduced glutamate affinity as compared to EAAC1 WT , and determined the glutamate concentration dependence of currents of the mixed transporter population. The data were consistent with two independent populations of transporters with apparent glutamate affinities similar to those of EAAC1 H295K and EAAC1 WT , respectively. Finally, we coexpressed EAAC1 WT with the pH-independent mutant transporter EAAC1 E373Q , showing two independent populations of transporters, one being pH dependent, the other being pH-independent. In conclusion, we propose that EAAC1 assembles as trimers of identical subunits, but that the individual subunits in the trimer function independently of each other.Plasma membrane glutamate transporters actively remove glutamate from the synaptic cleft after excitatory neurotransmission is complete. Uptake into the cells surrounding the synapse against a glutamate concentration gradient is achieved by these transporters by coupling transmembrane glutamate movement to the cotransport of three sodium ions and one proton, and the countertransport of one potassium ion (1,2). In addition to the movement of ions across the membrane being directly coupled to glutamate transport, glutamate transporters also catalyze uncoupled transmembrane flux of anions (3). This anion conductance is thought to be an integral property of the transporters and is not mediated by indirect coupling of transport to a secondary anion channel (3-5).Address correspondence to: Christof Grewer, PhD, Department of Physiology and Biophysics, University of Miami School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136; Phone: (305) 243-1021; Fax: (305) The mammalian glutamate transporters belong to a large family of membrane transport proteins that comprise also neutral amino acid transporters, such as the alanine serine cysteine transporters (ASCTs (6,7)), and dicarboxylate transporters (8,9). A large number of biochemical data from both mammalian (10,11) and bacterial glutamate transporters (12,13), as well as recent crystallographic evidence f...

The quantum mechanical treatment of both electrons and nuclei is crucial in nonadiabatic dynamical processes such as proton-coupled electron transfer. The nuclear−electronic orbital (NEO) method provides an elegant framework for including nuclear quantum effects beyond the Born–Oppenheimer approximation. To enable the study of nonequilibrium properties, we derive and implement a real-time NEO (RT-NEO) approach based on time-dependent Hatree-Fock or density functional theory, in which the electronic and nuclear degrees of freedom are propagated in a time-dependent variational framework. Nuclear and electronic spectral features can be resolved from the time-dependent dipole moment computed using the RT-NEO method. The test cases show the dynamical interplay between the quantum nuclei and the electrons through vibronic coupling. Moreover, vibrational excitation in the RT-NEO approach is demonstrated by applying a resonant driving field, and electronic excitation is demonstrated by simulating excited state intramolecular proton transfer. This work shows that the RT-NEO approach is a promising tool to study nonadiabatic quantum dynamical processes within a time-dependent variational description for the coupled electronic and nuclear degrees of freedom.

Glutamate transport by the excitatory amino acid carrier EAAC1 is known to be reversible. Thus, glutamate can either be taken up into cells, or it can be released from cells through reverse transport, depending on the electrochemical gradient of the co-and countertransported ions. However, it is unknown how fast and by which reverse transport mechanism glutamate can be released from cells. Here, we determined the steady-and pre-steady-state kinetics of reverse glutamate transport with submillisecond time resolution. First, our results suggest that glutamate and Na ؉ dissociate from their cytoplasmic binding sites sequentially, with glutamate dissociating first, followed by the three cotransported Na ؉ ions. Second, the kinetics of glutamate transport depend strongly on transport direction, with reverse transport being faster but less voltage-dependent than forward transport. Third, electrogenicity is distributed over several reverse transport steps, including intracellular Na ؉ binding, reverse translocation, and reverse relocation of the K ؉ -bound EAAC1. We propose a kinetic model, which is based on a ''first-in-first-out'' mechanism, suggesting that glutamate association, with its extracellular binding site as well as dissociation from its intracellular binding site, precedes association and dissociation of at least one Na ؉ ion. Our model can be used to predict rates of glutamate release from neurons under physiological and pathophysiological conditions. excitatory amino acid transporter ͉ electrophysiology ͉ reverse transport ͉ patch-clamp ͉ caged compounds G lutamate transporters belong to the class of Na ϩ -driven secondary-active transporters. They couple the uphill uptake of glutamate into cells to the movement of three Na ϩ ions down their ion concentration gradient (1). Neurons, like many other cells, express glutamate transporters, allowing them to keep a 10 6 -fold glutamate concentration gradient across their cell membranes (2). This steep concentration gradient is essential for neuronal signaling, because it ensures submicromolar resting concentrations of extracellular glutamate.Glutamate transporters are not strictly unidirectional and are able to change the direction of glutamate transport (3). Under physiological conditions, forward transport from the extracellular side to the cytosol is favored. However, if the driving force for glutamate uptake decreases, glutamate can be released from cells through reverse glutamate transport (3, 4). This situation may arise in oxygen-deprived cells when the Na ϩ concentration gradient across the membrane runs down, and/or when cells depolarize. In ischemic neurons, the majority of glutamate release upon oxygen/glucose deprivation was shown to be caused by reverse glutamate transport and not by vesicular release (5, 6). Considering the severe neurotoxic effects of elevated extracellular glutamate concentrations, it is of major importance to understand the mechanism of how glutamate is released through reverse transport.Here, we investigated with high time re...

The glutamate transporter excitatory amino acid carrier 1 (EAAC1) catalyzes the co-transport of three Na

The recently developed real-time nuclear–electronic orbital (RT-NEO) approach provides an elegant framework for treating electrons and selected nuclei, typically protons, quantum mechanically in nonequilibrium dynamical processes. However, the RT-NEO approach neglects the motion of the other nuclei, preventing a complete description of the coupled nuclear–electronic dynamics and spectroscopy. In this work, the dynamical interactions between the other nuclei and the electron–proton subsystem are described with the mixed quantum–classical Ehrenfest dynamics method. The NEO-Ehrenfest approach propagates the electrons and quantum protons in a time-dependent variational framework, while the remaining nuclei move classically on the corresponding average electron–proton vibronic surface. This approach includes the non-Born–Oppenheimer effects between the electrons and the quantum protons with RT-NEO and between the classical nuclei and the electron–proton subsystem with Ehrenfest dynamics. Spectral features for vibrational modes involving both quantum and classical nuclei are resolved from the time-dependent dipole moments. This work shows that the NEO-Ehrenfest method is a powerful tool to study dynamical processes with coupled electronic and nuclear degrees of freedom.