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In this study we investigate the Diels–Alder reaction between methyl acrylate and butadiene, which is catalyzed by BF3 Lewis acid in explicit water solution, using URVA and Local Mode Analysis as major tools complemented with NBO, electron density and ring puckering analyses. We considered four different starting orientations of methyl acrylate and butadiene, which led to 16 DA reactions in total. In order to isolate the catalytic effects of the BF3 catalyst and those of the water environment and exploring how these effects are synchronized, we systematically compared the non-catalyzed reaction in gas phase and aqueous solution with the catalyzed reaction in gas phase and aqueous solution. Gas phase studies were performed at the B3LYP/6-311+G(2d,p) level of theory and studies in aqueous solution were performed utilizing a QM/MM approach at the B3LYP/6-311+G(2d,p)/AMBER level of theory. The URVA results revealed reaction path curvature profiles with an overall similar pattern for all 16 reactions showing the same sequence of CC single bond formation for all of them. In contrast to the parent DA reaction with symmetric substrates causing a synchronous bond formation process, here, first the new CC single bond on the CH2 side of methyl acrylate is formed followed by the CC bond at the ester side. As for the parent DA reaction, both bond formation events occur after the TS, i.e., they do not contribute to the energy barrier. What determines the barrier is the preparation process for CC bond formation, including the approach diene and dienophile, CC bond length changes and, in particular, rehybridization of the carbon atoms involved in the formation of the cyclohexene ring. This process is modified by both the BF3 catalyst and the water environment, where both work in a hand-in-hand fashion leading to the lowest energy barrier of 9.06 kcal/mol found for the catalyzed reaction R1 in aqueous solution compared to the highest energy barrier of 20.68 kcal/mol found for the non-catalyzed reaction R1 in the gas phase. The major effect of the BF3 catalyst is the increased mutual polarization and the increased charge transfer between methyl acrylate and butadiene, facilitating the approach of diene and dienophile and the pyramidalization of the CC atoms involved in the ring formation, which leads to a lowering of the activation energy. The catalytic effect of water solution is threefold. The polar environment leads also to increased polarization and charge transfer between the reacting species, similar as in the case of the BF3 catalyst, although to a smaller extend. More important is the formation of hydrogen bonds with the reaction complex, which are stronger for the TS than for the reactant, thus stabilizing the TS which leads to a further reduction of the activation energy. As shown by the ring puckering analysis, the third effect of water is space confinement of the reacting partners, conserving the boat form of the six-member ring from the entrance to the exit reaction channel. In summary, URVA combined with LMA has led to a clearer picture on how both BF3 catalyst and aqueous environment in a synchronized effort lower the reaction barrier. These new insights will serve to further fine-tune the DA reaction of methyl acrylate and butadiene and DA reactions in general.
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Assessing the Catalytic Role of Native Glucagon Amyloid Fibrils
Glucagon stands out as a pivotal peptide hormone, instrumental in controlling blood glucose levels and lipid metabolism. While the formation of glucagon amyloid fibrils has been documented, their biological functions remain enigmatic. Recently, we demonstrated experimentally that glucagon amyloid fibrils can act as catalysts in several biological reactions including esterolysis, lipid hydrolysis, and dephosphorylation. Herein, we present a multiscale quantum mechanics/molecular mechanics (QM/MM) simulation of the acylation step in the esterolysis of para-nitrophenyl acetate (p-NPA), catalyzed by native glucagon amyloid fibrils, serving as a model system to elucidate their catalytic function. This step entails a concerted mechanism, involving proton transfer from serine to histidine, followed by the nucleophilic attack of the serine oxy anion on the carbonyl carbon of p-NPA. We computed the binding energy and free-energy profiles of this reaction using the protein-dipole Langevin-dipole (PDLD) within the linear response approximation (LRA) framework (PDLD/S-LRA-2000) and the empirical valence bond (EVB) methods. This included simulations of the reaction in an aqueous environment and in the fibril, enabling us to estimate the catalytic effect of the fibril. Our EVB calculations obtained a barrier of 23.4 kcal mol-1 for the enzyme-catalyzed reaction compared to the experimental value of 21.9 kcal mol-1 (and a calculated catalytic effect of 3.2 kcal mol-1 compared to the observed effect of 4.7 kcal mol-1). This close agreement together with the barrier reduction when transitioning from the reference solution reaction to the amyloid fibril provides supporting evidence to the catalytic role of glucagon amyloid fibrils. Moreover, employing the PDLD/S-LRA-2000 approach further reinforced exclusively the enzyme's catalytic role. The results presented in this study contribute significantly to our understanding of the catalytic role of glucagon amyloid fibrils, marking, to the best of our knowledge, the first-principles mechanistic investigation of fibrils using QM/MM methods. Therefore, our findings offer fruitful insights for future research into the mechanisms of related amyloid catalysis.
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- Award ID(s):
- 2142727
- PAR ID:
- 10502370
- Publisher / Repository:
- ACS Catalysis
- Date Published:
- Journal Name:
- ACS Catalysis
- Volume:
- 14
- Issue:
- 7
- ISSN:
- 2155-5435
- Page Range / eLocation ID:
- 4656 to 4664
- Subject(s) / Keyword(s):
- amyloid fibrils binding energy catalysis kinetics mechanisms peptides and proteins.
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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The catalytic effects of iridium pincer complexes for the hydrogenation of carbon dioxide were investigated with the Unified Reaction Valley Approach (URVA), exploring the reaction mechanism along the reaction path traced out by the reacting species on the potential energy surface. Further details were obtained with the Local Mode Analysis performed at all stationary points, complemented by the Natural Bond Orbital and Bader’s Quantum Atoms in Molecules analyses. Each of the five reaction paths forming the catalytic cycle were calculated at the DFT level complemented with DLPNO-CCSD(T) single point calculations at the stationary points. For comparison, the non-catalytic reaction was also investigated. URVA curvature profiles identified all important chemical events taking place in the non-catalyzed reaction and in the five reactions forming the catalytic cycle, and their contribution to the activation energy was disclosed. The non-catalytic reaction has a large unfavorable activation energy of 76.3 kcal/mol, predominately caused by HH bond cleave in the H2 reactant. As shown by our study, the main function of the iridium pincer catalyst is to split up the one–step non-catalytic reaction into an energy efficient multistep cycle, where HH bond cleavage is replaced by the cleavage of a weaker IrH bond with a small contribution to the activation energy. The dissociation of the final product from the catalyst requires the cleavage of an IrO bond, which is also weak, and contributes only to a minor extent to the activation energy. This, in summary, leads to the substantial lowering of the overall activation barrier by about 50 kcal/mol for the catalyzed reaction. We hope that this study inspires the community to add URVA to their repertoire for the investigation of catalysis reactions.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acscatal.4c00452
