Application Of Combined QM/MM Method In Elucidating Solvent Effects Of Decarboxylation Reaction And Mechanism Of Disulfide Bond Exchange Reaction In Aqueous And Protein Environment

The decarboxylation of organic carboxylic acids is widely used in petroleum,chemical,biological and other fields.In recent decades,the decarboxylation reaction mechanism of carboxylic acids has become a hot spot in organic chemistry research.The frequent occurrence of decarboxylation reactions in the degradation and synthesis processes of organic chemistry,as well as the enzymatic reactions of biochemistry,and the use of decarboxylation reactions to illustrate the basic principles of reaction kinetics in solution are sufficient to illustrate the importance of decarboxylation reactions.Organic chemists have long realized the value of decarboxylation and used it as a standard method for molecular degradation and synthesis.At the same time,physical chemists have studied the decarboxylation rate of organic acids in solution and used the results in the theory of single-molecule reactions.The mechanism of thermal decarboxylation was clarified by combining organic and physical methods.There are a lot of data on the experimental aspect and the thermodynamics and kinetic mechanism of the decarboxylation reaction.However,the microscopic aspect,the influence of different solvents and reaction conditions on the decarboxylation mechanism and the physical nature of the mechanism require the assistance of theoretical computational chemists.Through theoretical calculations to explore the substituent effects,solvent effects and enzyme effects that affect the decarboxylation reaction and its reverse reaction:the capture rate of carbon dioxide,will help experimental chemists find out the experimental conditions that promote the decarboxylation reaction,and materials chemists design new types Materials used for greenhouse gas capture,and enzyme chemists have revealed the catalytic mechanism of enzymes.The formation of disulfide bonds plays an important role in the correct folding of disordered secret proteins.Incorrectly paired cysteines can cause non-native folding of secreted proteins,leading to biological dysfunction.Therefore,it is necessary to study the mechanism of disulfide bond formation and even correct folding in enzymes.The main mechanism for the formation of disulfide bonds is the exchange of deprotonated cysteine and disulfide bonds.This reaction is an"atypical"S_N2 mechanism.In order to oxidize the disulfide bonds in the secreted protein and make it fold correctly,prokaryotic cells mainly rely on Dsbprotein to complete the entire oxidation cycle,and eukaryotic cells mainly rely on PDI protein to play that role.Among them,in prokaryotic cells,the Dsbproteins cooperate closely,the oxidation path is responsible for the non-selective introduction of disulfide bonds,and the isomerization path is responsible for error correction,which are respectively transmitted to the final electron acceptor.The transfer of disulfide bonds in this cell body has been studied for many years,and the mechanism has been relatively clarified.Since many mechanisms between cell bodies are similar,studying this mechanism will help to understand the mechanism of disulfide bond transfer in eukaryotic cells.1.Solvation Induction of Free Energy Barriers of Decarboxylation Reactions in Aqueous Solution from Dual-Level QM/MM SimulationsCarbon dioxide capture,corresponding to the recombination process of decarboxylation reactions of organic acids,is typically barrierless in the gas phase and has a relatively low barrier in aprotic solvents.However,these processes often encounter significant solvent-reorganization-induced barriers in aqueous solution if the decarboxylation product is not immediately protonated.Both the intrinsic stereoelectronic effects and solute-solvent interactions play critical roles in determining the overall decarboxylation equilibrium and free energy barrier.An understanding of the interplay of these factors is important for designing novel materials applied to greenhouse gas capture and storage as well as for unraveling the catalytic mechanisms of a range of carboxy lyases in biological CO₂ production.A range of decarboxylation reactions of organic acids with rates spanning nearly 30 orders of magnitude have been examined through dual-level combined quantum mechanical and molecular mechanical simulations to help elucidate the origin of solvation-induced free energy barriers for decarboxylation and the reverse carboxylation reactions in water.2.Origin of Free Energy Barriers of Decarboxylation and the Reverse Process of CO₂ Capture in Dimethylformamide and in Water.In aqueous solution,biological decarboxylation reactions proceed irreversibly to completion,whereas the reverse carboxylation processes are typically powered by the hydrolysis of ATP.The exchange of the carboxylate of ring-substituted arylacetates with isotope-labeled CO₂ in polar aprotic solvents reported recently suggests a dramatic change in the partition of reaction pathways.Yet,there is little experimental data pertinent to the kinetic barriers for protonation and thermodynamic data on CO₂ capture by the carbanions of decarboxylation reactions.Employing a combined quantum mechanical and molecular mechanical simulation approach,we investigated the decarboxylation reactions of a series of organic carboxylate compounds in aqueous and in dimethylformamide solutions,revealing that the reverse carboxylation barriers in solution are fully induced by solvent effects.A linear Bell-Evans-Polanyi relationship was found between the rates of decarboxylation and the Gibbs energies of reaction,indicating diminishing recombination barriers in DMF.In contrast,protonation of the carbanions by the DMF solvent has large free energy barriers,rendering the competing exchange of isotope-labeled CO₂ reversible in DMF.The finding of an intricate interplay of carbanion stability and solute-solvent interaction in decarboxylation and carboxylation could be useful to designing novel materials for CO₂ capture.3.In depth study of thiolate-disulfide model exchange reaction with a view of application to bioproteinsDisulfide bridge formation play an important role in the correctly folding of disordered protein.It is quite necessary to deeply explore the mechanism of this reaction by theoretical computation.Seeking for a appreciate method which is efficient and precise and can be used for protein simulation is more required.We devote to screen out such method to accomplish its application in protein thiolate-disulfide exchange reaction mechanism simulation.We constructed gas-phase MEP to testify the performance of density function and SCC-DFTB3 and proved to be A-E mechanism in gas-phase.We optimized the QM(DFTB3)/MM vd W parameters based on QM(CCSD(T))intermolecular interaction energy and use these new vd W parameters to do solution phase simulation.The mechanism turns from the slightly A-E mechanism to S_N2 mechanism and the free energy barrier 10 kcal/mol^-1.The calculated free energy barrier under QM(M11-L/6-31g(d))/MM potential is 14 kcal/mol^-1 and corrected to10.9 kcal/mol^-1 based on the error of gas-phase MEP.This result testified that QM(SCC-DFTB3)/MM with optimized vd W parameters is trustable for thiolate-disulfide exchange reactions in protein.4.Mechanism study of the oxidation of DsbA by DsbBDsbA is the most oxidizing periplasmic protein of the thioredoxin superfamily.It is reduced after continuous oxidation of secreted proteins.To maintain the balance of the overall redox system,DsbA needs to be reoxidized to restore its activity.DsbB is a membrane-embeded protein,which completes the reoxidation of DsbA through the cooperation of two pairs of cysteines on two periplasmic loops.Based on the two possible mechanisms proposed experimentally,starting from the intermolecular disulfide-bonded crystalline structure,we investigated the two cases separately.For the fast reaction,to release the oxidized state of DsbA,the buried Cys33 in the protein needs to be deprotonated to be activated.By analyzing the simulation trajectory,we found that the proton on Cys33 needs to pass through the water bridge to the nearby carboxyl oxygen of Glu24 before nucleophilic attack on Cys30-Cys104.The free energy barrier of the whole reaction is about 15kcal/mol for the fast reaction,the free Cys130 approaches Cys41-Cys44 before attacking,the energy barrier of this process is about 12kcal/mol.