Combining Complex Conjugation, Time-Reversal, and Spin-Flip Symmetry Projection of Coupled Cluster Wave Functions.

Complex conjugation symmetry breaking and restoration generates two nonorthogonal configurations at the Hartree-Fock level that can capture static correlation naturally. In conjunction with broken spin-symmetry coupled cluster theory, the symmetry-projected wave function shows good agreement with full configuration interaction in beryllium hydride insertion, lithium fluoride dissociation, and symmetric stretching of tetrahedral H4. By adding spin flip projection, we can also recover time reversal symmetry in the same coupled cluster framework. We also show results including point group symmetry projection.

A power series approximation in symmetry projected coupled cluster theory.

Projected Hartree-Fock theory provides an accurate description of many kinds of strong correlations but does not properly describe weakly correlated systems. On the other hand, single-reference methods, such as configuration interaction or coupled cluster theory, can handle weakly correlated problems but cannot properly account for strong correlations. Ideally, we would like to combine these techniques in a symmetry-projected coupled cluster approach, but this is far from straightforward. In this work, we provide an alternative formulation to identify the so-called disentangled cluster operators, which arise when we combine these two methodological strands. Our formulation shows promising results for model systems and small molecules.

Inactivation of the Lateral Hypothalamus Attenuates Methamphetamine-Induced Conditioned Place Preference through Regulation of Kcnq3 Expression.

Repeated administration of methylamphetamine (MA) induces MA addiction, which is featured by awfully unpleasant physical and emotional experiences after drug use is terminated. Neurophysiological studies show that the lateral hypothalamus (LH) is involved in reward development and addictive behaviors. Here, we show that repeated administration of MA activates the expression of c-Fos in LH neurons responding to conditioned place preference (CPP). Chemogenetic inhibition of the LH can disrupt the addiction behavior, demonstrating that the LH plays an important role in MA-induced reward processing. Critically, MA remodels the neurons of LH synaptic plasticity, increases intracellular calcium level, and enhances spontaneous current and evoked potentials of neurons compared to the saline group. Furthermore, overexpression of the potassium voltage-gated channel subfamily Q member 3 (Kcnq3) expression can reverse the CPP score and alleviate the occurrence of addictive behaviors. Together, these results unravel a new neurobiological mechanism underlying the MA-induced addiction in the lateral hypothalamus, which could pave the way toward new and effective interventions for this addiction disease.

Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway.

Nicotinamide adenine dinucleotide (NADH) has been reported to regulate synaptic plasticity recently, while its role in this process remains unclear. To explore the contribution and the underlying mechanisms of NADH regulating synaptic plasticity, here, we examined NADH's effect on immediate-early response genes (IEGs) expressions, including C-Fos and Arc in primary cultured cortical neurons and the frontal cortex of mouse brain. Our results showed that NADH promoted IEGs expression and that the C-Fos and Arc levels are increased in primary cultured cortical neurons, which is almost completely blocked by N-methyl-D-aspartate receptor (NMDAR) inhibitor, MK-801. Moreover, NADH significantly increased intracellular Ca2+ levels and the phosphorylation of Erk1/2, a downstream molecule of the NMDAR. Furthermore, NADH also significantly increased IEGs expression in vivo, accompanied by the changes of Ca2+ in neurons and activation of excitatory neurons in the mouse frontal cortex. In conclusion, this study indicates that NADH can promote the expression of synaptic plasticity-related IEGs through the NMDAR/Ca2+/Erk1/2 pathway, which provides a new way to understand the regulatory role of NADH in synaptic plasticity.

Principles Governing Catalytic Activity of Self-Assembled Short Peptides.

Molecular self-assembly provides a chemical strategy for the synthesis of nanostructures by using the principles of nature, and peptides serve as the promising building blocks to construct adaptable molecular architectures. Recently, a series of heptapeptides with alternative hydrophobic and hydrophilic residues were reported to form amyloid-like structures, which are capable of catalyzing acyl ester hydrolysis with remarkable efficiency. However, information remains elusive about the atomic structures of the fibrils. What is the origin of the sequence-dependent catalytic activity? How is the ester hydrolysis catalyzed by the fibrils? In this work, the atomic structures of the aggregates were determined by using molecular modeling and further validated by solid-state NMR experiments, where the fibril with high activity adopts twisted parallel configuration within each layer, and the one with low activity is in flat antiparallel configuration. The polymorphism originates from the interactions between different regions of the building block peptides, where the delicate balance between rigidity and flexibility plays an important role. We further show that the p-nitrophenylacetate ( pNPA) hydrolysis reactions catalyzed by two different fibrils follow a similar mechanism, and the difference in microenvironment at the active site between the natural enzyme and the present self-assembled fibrils should account for the discrepancy in catalytic activities. The present work provides understanding of the structure and function of self-assembled fibrils formed with short peptides at an atomic level and thus sheds new insight on designing aggregates with better functions.

A Two-Ended Data-Driven Accelerated Sampling Method for Exploring the Transition Pathways between Two Known States of Protein.

Conformational transitions of protein between different states are often associated with their biological functions. These dynamic processes, however, are usually not easy to be well characterized by experimental measurements, mainly because of inadequate temporal and spatial resolution. Meantime, sampling of configuration space with molecular dynamics (MD) simulations is still a challenge. Here we proposed a robust two-ended data-driven accelerated (teDA2) conformational sampling method, which drives the structural change in an adaptively updated feature space without introducing a bias potential. teDA2 was applied to explore adenylate kinase (ADK), a model with well characterized "open" and "closed" states. A single conformational transition event of ADK could be achieved within only a few or tens of nanoseconds sampled with teDA2. By analyzing hundreds of transition events, we reproduced different mechanisms and the associated pathways for domain motion of ADK reported in the literature. The multiroute characteristic of ADK was confirmed by the fact that some metastable states identified with teDA2 resemble available crystal structures determined at different conditions. This feature was further validated with Markov state modeling with independent MD simulations. Therefore, our work provides strong evidence for the conformational plasticity of protein, which is mainly due to the inherent degree of flexibility. As a reliable and efficient enhanced sampling protocol, teDA2 could be used to study the dynamics between functional states of various biomolecular machines.

Toward a Model for Activation of Orai Channel.

Store-operated calcium release-activated calcium (CRAC) channels mediate a variety of cellular signaling functions. The CRAC channel pore-forming protein, Orai1, is a hexamer arranged with 3-fold symmetry. Despite its importance in moving Ca2+ ions into cells, a detailed mechanistic understanding of Orai1 activation is lacking. Herein, a working model is proposed for the putative open state of Orai from Drosophila melanogaster (dOrai), which involves a "twist-to-open" gating mechanism. The proposed model is supported by energetic, structural, and experimental evidence. Fluorescent imaging demonstrates that each subunit on the intracellular side of the pore is inherently strongly cross-linked, which is important for coupling to STIM1, the pore activator, and graded activation of the Orai1 channel. The proposed model thus paves the way for understanding key aspects of calcium signaling at a molecular level.

Accurate Prediction of NMR Chemical Shifts in Macromolecular and Condensed-Phase Systems with the Generalized Energy-Based Fragmentation Method.

The generalized energy-based fragmentation (GEBF) method is extended to allow calculations of nuclear magnetic resonance (NMR) chemical shifts of macromolecular and condensed-phase systems feasible at a low computational cost. In this approach, NMR shielding constants in a large system are evaluated as a linear combination of the corresponding quantities from a series of small "electrostatically embedded" subsystems. Comparison of NMR shielding constants from the GEBF-X method [where X is an electronic structure method, such as Hartree-Fock (HF), density functional theory (DFT), ...] with those from the conventional quantum chemistry method for two representative systems verifies that the GEBF approach can reproduce the results of the conventional quantum chemistry method very well. This procedure has further been applied to compute NMR shielding constants of a large foldamer and a supramolecular aggregate, and the 15N shielding constant for CH3CN in the CHCl3 solvent. For the former two systems, the predicted 1H chemical shifts are in good agreement with the experimental data. For the CH3CN/CHCl3 solution, the 15N shielding constant of CH3CN is evaluated as the ensemble average of up to 200 sufficiently large CH3CN/CHCl3 clusters from either classical or QM/MM (quantum mechanics/molecular mechanics) molecular dynamics (MD) simulations. Our results reveal that the gas-to-solution shift of 15N (from an isolated CH3CN to the CH3CN/CHCl3 solution) based on PM6-DH+/MM MD simulation is in good accord with the experimental value, outperforming those based on classical MD simulation and the previous polarizable continuum model using integral equation formalism (IEF-PCM) study. This study unravels that the generation of representative liquid structures is critical in evaluating the NMR shielding constants of condensed-phase systems.