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Quantum Mechanics/molecular Mechanics (quantum + molecular_mechanic)
Selected AbstractsBifunctional Catalysis by Natural Cinchona Alkaloids: A Mechanism ExplainedCHEMISTRY - A EUROPEAN JOURNAL, Issue 32 2009Clotilde Abstract The use of bifunctional chiral catalysts, which are able to simultaneously bind and activate two reacting partners, currently represents an efficient and reliable strategy for the stereoselective preparation of valuable chiral compounds. Cinchona alkaloids such as quinine and quinidine, simple organic molecules generously provided by Nature, were the first compounds to be proposed to operate through a cooperative catalysis. To date, a full mechanistic characterization of the dual catalysis mode of cinchona alkaloids has proven a challenging objective, due to the transient, non-covalent nature of the involved catalyst,substrate interactions. Here, we propose a mechanistic rationale on how natural cinchona alkaloids act as efficient bifunctional catalysts by using a broad range of computational methods, including classical molecular dynamics, a mixed quantum mechanical/molecular mechanics (QM/MM) approach, and correlated ab-initio calculations. We also unravel the origin of enantio- and diastereoselectivity, which is due to a specific network of hydrogen bonds that stabilize the transition state of the rate-determining step. The results are validated by experimental evidence. [source] [Fe-Fe]-hydrogenase reactivated by residue mutations as bridging carbonyl rearranges: A QM/MM studyINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 14 2010Stefan Motiu Abstract In this work, we found aqueous enzyme phase reaction pathways for the reactivation of the exogenously inhibited [Fe-Fe]-hydrogenases by O2, or OH,, which metabolizes to H2O (Dogaru et al., Int J Quantum Chem 2008, 108; Motiu et al., Int J Quantum Chem 2007, 107, 1248). We used the hybrid quantum mechanics/molecular mechanics (QM/MM) method to study the reactivation pathways of the exogenously inhibited enzyme matrix. The ONIOM calculations performed on the enzyme agree with experimental results (Liu et al., J Am Chem Soc 2002, 124, 5175), that is, wild-type [Fe-Fe]-hydrogenase H-cluster is inhibited by oxygen metabolites. An enzyme spherical region with a radius of 8 Å (from the distal iron, Fed) has been screened for residues that prevent H2O from leaving the catalytic site and reactivate the [Fe-Fe]-hydrogenase H-cluster. In the screening process, polar residues were removed, one at a time, and frequency calculations provided the change in the Gibbs' energy for the dissociation of water (due to their deletion). When residue deletion resulted in significant Gibbs' energy decrease, further residue substitutions have been carried out. Following each substitution, geometry optimization and frequency calculations have been performed to assess the change in the Gibbs' energy for the elimination of H2O. Favorable thermodynamic results have been obtained for both single residue removal (,G,Glu374 = ,1.6 kcal/mol), single substitution (,GGlu374His = ,3.1 kcal/mol), and combined residue substitutions (,GArg111Glu;Thr145Val;Glu374His;Tyr375Phe = ,7.5 kcal/mol). Because the wild-type enzyme has only an endergonic step to overcome, that is, for H2O removal, by eliminating several residues, one at a time, the endergonic step was made to proceed spontaneously. Thus, the most promising residue deletions which enhance H2O elimination are ,Arg111, ,Thr145, ,Ser177, ,Glu240, ,Glu374, and ,Tyr375. The thermodynamics and electronic structure analyses show that the bridging carbonyl (COb) of the H-cluster plays a concomitant role in the enzyme inhibition/reactivation. In gas phase, COb shifts towards Fed to compensate for the electron density donated to oxygen upon the elimination of H2O. However, this is not possible in the wild-type enzyme because the protein matrix hinders the displacement of COb towards Fed, which leads to enzyme inhibition. Nevertheless, enzyme reactivation can be achieved by means of appropriate amino acid substitutions. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [source] Ab initio QM/MM dynamics of H3O+ in waterJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 14 2006Pathumwadee Intharathep Abstract A molecular dynamics (MD) simulation based on a combined ab initio quantum mechanics/molecular mechanics (QM/MM) method has been performed to investigate the solvation structure and dynamics of H3O+ in water. The QM region is a sphere around the central H3O+ ion, and contains about 6,8 water molecules. It is treated at the Hartree-Fock (HF) level, while the rest of the system is described by means of classical pair potentials. The Eigen complex (H9O) is found to be the most prevalent species in the aqueous solution, partly due to the selection scheme of the center of the QM region. The QM/MM results show that the Eigen complex frequently converts back and forth into the Zundel (H5O) structure. Besides the three nearest-neighbor water molecules directly hydrogen-bonded to H3O+, other neighbor waters, such as a fourth water molecule which interacts preferentially with the oxygen atom of the hydronium ion, are found occasionally near the ion. Analyses of the water exchange processes and the mean residence times of water molecules in the ion's hydration shell indicate that such next-nearest neighbor water molecules participate in the rearrangement of the hydrogen bond network during fluctuative formation of the Zundel ion and, thus, contribute to the Grotthuss transport of the proton. © 2006 Wiley Periodicals, Inc. J Comput Chem, 2006 [source] Specific force field parameters determination for the hybrid ab initio QM/MM LSCF methodJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2002Nicolas Ferré Abstract The pure quantum mechanics method, called Local Self-Consistent Field (LSCF), that allows to optimize a wave function within the constraint that some predefined spinorbitals are kept frozen, is discussed. These spinorbitals can be of any shape, and their occupation numbers can be 0 or 1. Any post-Hartree,Fock method, based on the restricted or unrestricted Hartree,Fock Slater determinant, and Kohn,Sham-based DFT method are available. The LSCF method is easily applied to hybrid quantum mechanics/molecular mechanics (QM/MM) procedure where the quantum and the classical parts are covalently bonded. The complete methodology of our hybrid QM/MM scheme is detailed for studies of macromolecular systems. Not only the energy but also the gradients are derived; thus, the full geometry optimization of the whole system is feasible. We show that only specific force field parameters are needed for a correct description of the molecule, they are given for some general chemical bonds. A careful analysis of the errors induced by the use of molecular mechanics in hybrid computation show that a general procedure can be derived to obtain accurate results at low computation effort. The methodology is applied to the structure determination of the crambin protein and to Menshutkin reactions between primary amines and chloromethane. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 610,624, 2002 [source] The Rate-Determining Step in the Rhodium,Xantphos-Catalysed Hydroformylation of 1-OcteneCHEMISTRY - A EUROPEAN JOURNAL, Issue 6 2008Erik Zuidema Dr. Abstract The rate-determining step in the hydroformylation of 1-octene, catalysed by the rhodium,Xantphos catalyst system, was determined by using a combination of experimentally determined 1H/2H and 12C/13C kinetic isotope effects and a theoretical approach. From the rates of hydroformylation and deuterioformylation, a small 1H/2H isotope effect of 1.2 was determined for the hydride moiety of the rhodium catalyst. 12C/13C isotope effects of 1.012(1) and 1.012(3) for the ,-carbon and ,-carbon atoms of 1-octene were determined, respectively. Both quantum mechanics/molecular mechanics (QM/MM) and full quantum mechanics calculations were carried out on the key catalytic steps, for "real-world" ligand systems, to clarify whether alkene coordination or hydride migration is the rate-determining step. Our calculations (21.4,kcal,mol,1) quantitatively reproduce the experimental energy barrier for CO dissociation (20.1,kcal,mol,1) starting at the (bisphosphane)RhH(CO)2 resting state. The barrier for hydride migration lies 3.8,kcal,mol,1 higher than the barrier for CO dissociation (experimentally determined trend ,3,kcal,mol,1). The computed 1H/2H and 12C/13C kinetic isotope effects corroborate the results of the energy analysis. [source] Analysis of Classical and Quantum Paths for Deprotonation of Methylamine by Methylamine DehydrogenaseCHEMPHYSCHEM, Issue 12 2007Kara E. Ranaghan Abstract The hydrogen-transfer reaction catalysed by methylamine dehydrogenase (MADH) with methylamine (MA) as substrate is a good model system for studies of proton tunnelling in enzyme reactions,an area of great current interest,for which atomistic simulations will be vital. Here, we present a detailed analysis of the key deprotonation step of the MADH/MA reaction and compare the results with experimental observations. Moreover, we compare this reaction with the related aromatic amine dehydrogenase (AADH) reaction with tryptamine, recently studied by us, and identify possible causes for the differences observed in the measured kinetic isotope effects (KIEs) of the two systems. We have used combined quantum mechanics/molecular mechanics (QM/MM) techniques in molecular dynamics simulations and variational transition state theory with multidimensional tunnelling calculations averaged over an ensemble of paths. The results reveal important mechanistic complexity. We calculate activation barriers and KIEs for the two possible proton transfers identified,to either of the carboxylate oxygen atoms of the catalytic base (Asp428,),and analyse the contributions of quantum effects. The activation barriers and tunnelling contributions for the two possible proton transfers are similar and lead to a phenomenological activation free energy of 16.5±0.9 kcal,mol,1 for transfer to either oxygen (PM3-CHARMM calculations applying PM3-SRP specific reaction parameters), in good agreement with the experimental value of 14.4 kcal,mol,1. In contrast, for the AADH system, transfer to the equivalent OD1 was found to be preferred. The structures of the enzyme complexes during reaction are analysed in detail. The hydrogen bond of Thr474,(MADH)/Thr172,(AADH) to the catalytic carboxylate group and the nonconserved active site residue Tyr471,(MADH)/Phe169,(AADH) are identified as important factors in determining the preferred oxygen acceptor. The protein environment has a significant effect on the reaction energetics and hence on tunnelling contributions and KIEs. These environmental effects, and the related clearly different preferences for the two carboxylate oxygen atoms (with different KIEs) in MADH/MA and AADH/tryptamine, are possible causes of the differences observed in the KIEs between these two important enzyme reactions. [source] Solvent and Protein Effects on the Structure and Dynamics of the Rhodopsin ChromophoreCHEMPHYSCHEM, Issue 9 2005Ute F. Röhrig Dr. Abstract The structure and dynamics of the retinal chromophore of rhodopsin are investigated systematically in different environments (vacuum, methanol solution, and protein binding pocket) and with different computational approaches (classical, quantum, and hybrid quantum mechanics/molecular mechanics (QM/MM) descriptions). Finite temperature effects are taken into account by molecular dynamics simulations. The different components that determine the structure and dynamics of the chromophore in the protein are dissected, both in the dark state and in the early photointermediates. In vacuum and in solution the chromophore displays a very high flexibility, which is significantly reduced by the protein environment. In the 11- cis chromophore, the bond-length alternation, which is correlated with the dipole moment, is found to be similar in solution and in the protein, while it differs greatly with respect to minimum-energy vacuum structures. In the model of the earliest protein photointermediate, the highly twisted chromophore shows a very reduced bond-length alternation. [source] | ||||||||||