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A highly accurate full-dimensional machine learning global potential energy surface for the rearrangement of methylhydroxycarbene (MHC, H3C–C–OH) was constructed, and the decay rate of MHC was evaluated with instanton rate theory based on this PES.

We performed extensive quasiclassical trajectory calculations for the H+C2D2→HD+C2D/D2+C2H reaction based on a recently developed, global and accurate potential energy surface by the fundamental-invariant neural network method. The direct abstraction pathway plays a minor role in the overall reactivity, which can be negligible as compared with the roaming pathways. The acetylene-facilitated roaming pathway dominates the reactivity, with very small contributions from the vinylidene-facilitated roaming. Although the roaming pathways proceed via the short-lived or long-lived complex forming process, the computed branching ratio of product HD to D2 is not far away from 2:1, implying roaming dynamics for this reaction is mainly contributed from the long-lived complex-forming process. The resulting angular distributions for the two product channels are also quite different. These computational results give valuable insights into the significance and isotope effects of roaming dynamics in the biomolecular reactions.

We report two novel roaming pathways for the H + C2H2 → H2 + C2H reaction by performing extensive quasiclassical trajectory calculations on a new, global, high-level machine learning-based potential energy surface. One corresponds to the acetylene-facilitated roaming pathway, where the H atom turns back from the acetylene + H channel and abstracts another H atom from acetylene. The other is the vinylidene-facilitated roaming, where the H atom turns back from the vinylidene + H channel and abstracts another H from vinylidene. The "double-roaming" pathways account for roughly 95% of the total cross section of the H2 + C2H products at the collision energy of 70 kcal/mol. These computational results give valuable insights into the significance of the two isomers (acetylene and vinylidene) in chemical reaction dynamics and also the experimental search for roaming dynamics in this bimolecular reaction.

Roaming is a novel mechanism in reaction dynamics. It describes an unusual pathway, which can be quite different from the conventional minimum-energy path, leading to products. While roaming has been reported or suggested in a number of unimolecular reactions, it has been rarely reported for bimolecular reactions. Here, we report a high-level computational study of roaming dynamics in the important bimolecular combustion reaction H + C2H4 → H2 + C2H3, using a new, high-level machine learning-based potential energy surface. In addition to the complex-mediated roaming mechanism, a non-complex forming roaming mechanism is found. It can be described as a direct inelastic collision where the departing H atom roams and then abstracts an H atom. We denoted this as “collision-induced” roaming. These two roaming mechanisms have different angular distributions; however, both produce highly internally excited C2H3. The roaming pathway leads to remarkably different dynamics as compared with the direct abstraction pathway. A clear signature of the roaming mechanism is highly internally excited C2H3, which could be observed experimentally.

Roaming is a novel mechanism in reaction dynamics. It describes an unusual pathway, which can be quite different from the conventional minimum-energy path, leading to products. While roaming has been reported or suggested in a number of unimolecular reactions, it has been rarely reported for bimolecular reactions. Here, we report a high-level computational study of roaming dynamics in the important bimolecular combustion reaction H + C2H4 → H2 + C2H3, using a new, high-level machine learning-based potential energy surface. In addition to the complex-mediated roaming mechanism, a non-complex forming roaming mechanism is found. It can be described as a direct inelastic collision where the departing H atom roams and then abstracts an H atom. We denoted this as “collision-induced” roaming. These two roaming mechanisms have different angular distributions; however, both produce highly internally excited C2H3. The roaming pathway leads to remarkably different dynamics as compared with the direct abstraction pathway. A clear signature of the roaming mechanism is highly internally excited C2H3, which could be observed experimentally., Collision-induced and complex-mediated roaming mechanisms are revealed for an important bimolecular reaction in combustion.

We report two novel roaming pathways for the H + C

The collisions transferring large portions of energy are often called supercollisions. In the H + C2H2 reactive system, the rovibrationally cold C2H2 molecule can be activated with substantial internal excitations by its collision with a translationally hot H atom. It is interesting to investigate the mechanisms of collisional energy transfer in other important reactions of H with hydrocarbons. Here, an accurate, global, full-dimensional potential energy surface (PES) of H + C2H4 was constructed by the fundamental invariant neural network fitting based on roughly 100 000 UCCSD(T)-F12a/aug-cc-pVTZ data points. Extensive quasi-classical trajectory calculations were carried out on the full-dimensional PES to investigate the energy transfer process in collisions of the translationally hot H atoms with C2H4 in a wide range of collision energies. The computed function of the energy-transfer probability is not a simple exponential decay function but exhibits large magnitudes in the region of a large amount of energy transfer, indicating the signature of supercollisions. The supercollisions among non-complex-forming nonreactive (prompt) trajectories are frustrated complex-forming processes in which the incoming H atom penetrates into C2H4 with a small C-H distance but promptly and directly leaves C2H4. The complex-forming supercollisions, in which either the attacking H atom leaves (complex-forming nonreactive collisions) or one of the original H atoms of C2H4 leaves (complex-forming reactive trajectories), dominate large energy transfer from the translational energy to internal excitation of molecule. The current work sheds valuable light on the energy transfer of this important reaction in the combustion and may motivate related experimental investigations.

In a super energy transfer process, a significant portion of the initial relative collision energy can be transferred to the internal vibrational energy of the target molecule through chemical complex formation. The phenomenon of super energy transfer for the H + C2H2 system is investigated in a collision energy region from 25 to 65 kcal/mol. Based on the quasi-classical trajectory calculations, it has been found that the super energy transfer can occur for all the collision energies considered. The chemical-complex-formation mechanism plays an essential role for the super energy transfer process. Additionally, the average energy transfer increases almost linearly with the collision energy.

The endoplasmic reticulum-Golgi intermediate compartment protein-53 (ERGIC-53, aka LMAN1), which cycles between the endoplasmic reticulum (ER) and Golgi, is a known cargo receptor for a number of soluble proteins. However, whether LMAN1 plays a role as a trafficking factor in the central nervous system is largely unknown. Here, we determined the role of LMAN1 on endogenous protein levels of the Cys-loop superfamily of neuroreceptors, including gamma-aminobutyric acid type A receptors (GABA(A)Rs), 5-hydroxytryptamine (serotonin) type 3 (5-HT(3)) receptors, and nicotinic acetylcholine receptors (nAChRs). Knockdown of LMAN1 reduces the surface trafficking of endogenous β3 subunits of GABA(A)Rs in mouse hypothalamic GT1-7 neurons. Furthermore, Western blot analysis of brain homogenates from LMAN1 knockout mice demonstrated that loss of LMAN1 decreases the total protein levels of 5HT(3)A receptors and γ2 subunits of GABA(A)Rs. LMAN1 knockout regulates the ER proteostasis network by upregulating ERP44 without changing calnexin levels. Interestingly, despite the critical role of the glycan-binding function of LMAN1 in its other known cargo clients, LMAN1 interacts with GABA(A)Rs in a glycan-independent manner. In summary, LMAN1 is a trafficking factor for certain neuroreceptors in the central nervous system. This is the first report of LMAN1 function in membrane protein trafficking.

Biogenesis of membrane proteins is controlled by the protein homeostasis (proteostasis) network. We have been focusing on protein quality control of γ-aminobutyric acid type A (GABAA) receptors, the major inhibitory neurotransmitter-gated ion channels in mammalian central nervous system. Proteostasis deficiency in GABAA receptors causes loss of their surface expression and thus function on the plasma membrane, leading to epilepsy and other neurological diseases. One well-characterized example is the A322D mutation in the α1 subunit that causes its extensive misfolding and expedited degradation in the endoplasmic reticulum (ER), resulting in autosomal dominant juvenile myoclonic epilepsy. We aimed to correct misfolding of the α1(A322D) subunits in the ER as an approach to restore their functional surface expression. Here, we showed that application of BIX, a specific, potent ER resident HSP70 family protein BiP activator, significantly increases the surface expression of the mutant receptors in human HEK293T cells and neuronal SH-SY5Y cells. BIX attenuates the degradation of α1(A322D) and enhances their forward trafficking and function. Furthermore, because BiP is one major target of the two unfolded protein response (UPR) pathways: ATF6 and IRE1, we continued to demonstrate that modest activations of the ATF6 pathway and IRE1 pathway genetically enhance the plasma membrane trafficking of the α1(A322D) protein in HEK293T cells. Our results underlie the potential of regulating the ER proteostasis network to correct loss-of-function protein conformational diseases.

GABAA receptors are the primary inhibitory ion channels in the mammalian central nervous system. The A322D mutation in the α1 subunit results in its excessive endoplasmic reticulum-associated degradation at the expense of plasma membrane trafficking, leading to autosomal dominant juvenile myoclonic epilepsy. Presumably, valosin-containing protein (VCP)/p97 extracts misfolded subunits from the endoplasmic reticulum membrane to the cytosolic proteasome for degradation. Here we showed that inhibiting VCP using Eeyarestatin I reduces the endoplasmic reticulum-associated degradation of the α1(A322D) subunit without an apparent effect on its dynamin-1 dependent endocytosis and that this treatment enhances its trafficking. Furthermore, coapplication of Eeyarestatin I and suberanilohydroxamic acid, a known small molecule that promotes chaperone-assisted folding, yields an additive restoration of surface expression of α1(A322D) subunits in HEK293 cells and neuronal SH-SY5Y cells. Consequently, this combination significantly increases GABA-induced chloride currents in whole-cell patch clamping experiments than either chemical compound alone in HEK293 cells. Our findings suggest that VCP inhibition without stress induction, together with folding enhancement, represents a new strategy to restore proteostasis of misfolding-prone GABAA receptors and, therefore, a potential remedy for idiopathic epilepsy.

The Cys-loop receptors play prominent roles in the nervous system. They include γ-aminobutyric acid type A receptors, nicotinic acetylcholine receptors, 5-hydroxytryptamine type-3 receptors, and glycine receptors. Proteostasis represents an optimal state of the cellular proteome in normal physiology. The proteostasis network regulates the folding, assembly, degradation, and trafficking of the Cys-loop receptors, ensuring their efficient functional cell surface expressions. Here, we summarize current advances about the protein biogenesis process of the Cys-loop receptors. Because operating on individual biogenesis steps influences the receptor cell surface level, manipulating the proteostasis network components can regulate the function of the receptors, representing an emerging therapeutic strategy for corresponding channelopathies.

The Cys-loop receptors play prominent roles in the nervous system. They include γ-aminobutyric acid type A receptors, nicotinic acetylcholine receptors, 5-hydroxytryptamine type-3 receptors, and glycine receptors. Proteostasis represents an optimal state of the cellular proteome in normal physiology. The proteostasis network regulates the folding, assembly, degradation, and trafficking of the Cys-loop receptors, ensuring their efficient functional cell surface expressions. Here, we summarize current advances about the protein biogenesis process of the Cys-loop receptors. Because operating on individual biogenesis steps influences the receptor cell surface level, manipulating the proteostasis network components can regulate the function of the receptors, representing an emerging therapeutic strategy for corresponding channelopathies.

Proteostasis maintenance of γ-aminobutyric acid type A (GABAA) receptors dictates their function in controlling neuronal inhibition in mammalian central nervous systems. However, as a multisubunit, multispan, integral membrane protein, even wild type subunits of GABAA receptors fold and assemble inefficiently in the endoplasmic reticulum (ER). Unassembled and misfolded subunits undergo ER-associated degradation (ERAD), but this degradation process remains poorly understood for GABAA receptors. Here, using the α1 subunits of GABAA receptors as a model substrate, we demonstrated that Grp94, a metazoan-specific Hsp90 in the ER lumen, uses its middle domain to interact with the α1 subunits and positively regulates their ERAD. OS-9, an ER-resident lectin, acts downstream of Grp94 to further recognize misfolded α1 subunits in a glycan-dependent manner. This delivers misfolded α1 subunits to the Hrd1-mediated ubiquitination and the valosin-containing protein-mediated extraction pathway. Repressing the initial ERAD recognition step by inhibiting Grp94 enhances the functional surface expression of misfolding-prone α1(A322D) subunits, which causes autosomal dominant juvenile myoclonic epilepsy. This study clarifies a Grp94-mediated ERAD pathway for GABAA receptors, which provides a novel way to finely tune their function in physiological and pathophysiological conditions.