Gas-phase DNA oligonucleotide structures. A QM/MM and atoms in molecules study

QM/MM calculations have been employed to investigate the role of hydrogen bonding and pi-stacking in single- and double-stranded DNA oligonucleotides. DFT calculations and Atoms in Molecules analysis on QM/MM-optimized structures allow characterization and estimation of the energies of pi-stacking and hydrogen-bond interactions. This shows that pi-stacking interactions depend on the number and the nature of the DNA bases for single-stranded nucleotides; for instance, guanines are found to be involved in strong hydrogen bonds, whereas adenines interact mainly via stacking interactions. The role of interbase hydrogen bonding was explored: the -NH2 groups of guanine, adenine, and cytosine participate in N-H...O and N-H...N interactions. These are much stronger in single-strand oligonucleotides, where the -NH2 groups are highly nonplanar. In double-stranded DNA, the strong base-pairing hydrogen bonds of complementary bases lead to more planar -NH2 groups, which tend to be involved in pi-stacking interactions rather than H-bonds. The use of AIM also allows us to evaluate the interplay of pi-stacking and H-bonding, suggesting that cooperativity does occur, but is generally limited to about 1-2 kcal/mol.     

The reaction mechanism of hydroxyethylphosphonate dioxygenase: a QM/MM study

By employing ab initio quantum mechanical/molecular mechanical (QM/MM) and molecular dynamics (MD) simulations, we have provided further evidence against the previously proposed hydroperoxylation or hydroxylation mechanism of hydroxyethylphosphonate dioxygenase (HEPD). HEPD employs an interesting catalytic cycle based on concatenated bifurcations. The first bifurcation is based on the abstraction of hydrogen atoms from the substrate, which leads to a distal or proximal hydroperoxo species (Fe-OOH or Fe-(OH)O). The second and the third bifurcations refer to the carbon-carbon bond cleavage reaction. And this is achieved through a tridentate intermediate, or employing a proton-shuttle assisted mechanism, in which the residue Glu(176) or the Fe(IV)=O group serves as a general base. The reaction directions seem to be tunable and show significant environment dependence. This mechanism can provide a comprehensive interpretation for the seemingly contradicting experimental evidences and provide insight into the development of biochemistry and material sciences.     

QM/MM study of the taxadiene synthase mechanism

Combined quantum mechanics/molecular mechanics (QM/MM) calculations were used to investigate the reaction mechanism of taxadiene synthase (TXS). TXS catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to taxadiene (T) and four minor cyclic products. All these products originate from the deprotonation of carbocation intermediates. The reaction profiles for the conversion of GGPP to T as well as to minor products were calculated for different configurations of relevant TXS carbocation complexes. The QM region was treated at the M06-2X/TZVP level, while the CHARMM27 force field was used to describe the MM region. The QM/MM calculations suggest a reaction pathway for the conversion of GGPP to T, which slightly differs from previous proposals regarding the number of reaction steps and the conformation of the carbocations. The QM/MM results also indicate that the formation of minor products via water-assisted deprotonation of the carbocations is highly exothermic, by about −7 to −23 kcal/mol. Curiously, however, the computed barriers and reaction energies indicate that the formation of some of the minor products is more facile than the formation of T. Thus, the present QM/MM calculations provide detailed insights into possible reaction pathways and into the origin of the promiscuity of TXS, but they do not reproduce the product distribution observed experimentally. © 2019 Wiley Periodicals, Inc.     

A QM/MM study of a nucleophilic aromatic substitution reaction catalyzed by 4-chlorobenzoyl-CoA dehalogenase

Calculated using a QM/MM method, the free energy profile for the conversion of 4-chlorobenzoate to 4-hydroxybenzoate catalyzed by 4-chlorobenzoyl-CoA dehalogenase indicates the existence of a stable Meisenheimer complex.     

A QM/MM study on the catalytic mechanism of pyruvate decarboxylase

Pyruvate decarboxylase (PDC) is a typical thiamin diphosphate (ThDP)-dependent enzyme with widespread applications in industry. Though studies regarding the reaction mechanism of PDC have been reported, they are mainly focused on the formation of ThDP ylide and some elementary steps in the catalytic cycle, studies about the whole catalytic cycle of PDC are still not completed. In these previous studies, a major controversy is whether the key active residues (Glu473, Glu50′, Asp27′, His113′, His114′) are protonated or ionized during the reaction. To explore the catalytic mechanism and the role of key residues in the active site, three whole-enzyme models were considered, and the combined QM/MM calculations on the nonoxidative decarboxylation of pyruvate to acetaldehyde catalyzed by PDC were performed. According to our computational results, the fundamental reaction pathways, the complete energy profiles of the whole catalytic cycle, and the specific role of key residues in the common steps were obtained. It is also found that the same residue with different protonation states will lead to different reaction pathways and energy profiles. The mechanism derived from the model in which the residues (Glu473, Glu50′, Asp27′, His113′, His114′) are in their protonated states is most consistent with experimental observations. Therefore, extreme care must be taken when assigning the protonation states in the mechanism study. Because the experimental determination of protonation state is currently difficult, the combined QM/MM method provides an indirect means for determining the active-site protonation state.     

Exploring SCC-DFTB paths for mapping QM/MM reaction mechanisms

A new first-order procedure for locating transition structures (TS) that employs hybrid quantum mechanical/molecular mechanical (QM/MM) potentials has been developed. This new technique (RPATh+RESD) combines the replica path method (RPATh) and standard reaction coordinate driving (RCD) techniques in an approach that both efficiently determines reaction barriers and successfully eliminates two key weaknesses of RCD calculations (i.e., hysteresis/discontinuities in the path and the sequential nature of the RCD procedure). In addition, we have extended CHARMM's QM/MM reaction pathway methods, the RPATh and nudged elastic band (NEB) methods, to incorporate SCC-DFTB wave functions. This newly added functionality has been applied to the chorismate mutase-catalyzed interconversion of chorismate to prephenate, which is a key step in the shikimate pathway of bacteria, fungi, and other higher plants. The RPATh+RESD barrier height (DeltaE=5.7 kcal/mol) is in good agreement with previous results from full-energy surface mapping studies (Zhang, X.; Zhang, X.; Bruice, T. C. Biochemistry 2005, 44, 10443-10448). Full reaction paths were independently mapped with RPATh and NEB methods and showed good agreement with the final transition state from the RPATh+RESD "gold standard" and previous high-level QM/MM transition states (Woodcock, H. L.; Hodoscek, M.; Gilbert, T. B.; Gill, P. M. W.; Schaefer, H. F.; Brooks, B. R. J. Comput. Chem. 2007, 28, 1485-1502). The SCC-DFTB TS geometry most closely approximates the MP2/6-31+G(d) QM/MM result. However, the barrier height is underestimated and possibly points to an area for improvement in SCC-DFTB parametrization. In addition, the steepest descents (SD) minimizer for the NEB method was modified to uncouple the in-path and off-path degrees of freedom during the minimization, which significantly improved performance. The convergence behavior of the RPATh and NEB was examined for SCC-DFTB wave functions, and it was determined that, in general, both methods converge at about the same rate, although the techniques used for convergence may be different. For instance, RPATh can effectively use the adopted basis Newton-Raphson (ABNR) minimizer, where NEB seems to require a combination of SD and ABNR.     

Combined QM/MM study of the opsin shift in bacteriorhodopsin

Combined quantum mechanical and molecular mechanical (QM/MM) calculations and molecular dynamics simulations of bacteriorhodopsin (bR) in the membrane matrix have been carried out to determine the factors that make significant contributions to the opsin shift. We found that both solvation and interactions with the protein significantly shifts the absorption maximum of the retinal protonated Schiff base, but the effects are much more pronounced in polar solvents such as methanol, acetonitrile, and water than in the protein environment. The differential solvatochromic shifts of PSB in methanol and in bR leads to a bathochromic shift of about 1800 cm(-1). Because the combined QM/MM configuration interaction calculation is essentially a point charge model, this contribution is attributed to the extended point-charge model of Honig and Nakanishi. The incorporation of retinal in bR is accompanied by a change in retinal conformation from the 6-s-cis form in solution to the 6-s-trans configuration in bR. The extension of the pi-conjugated system further increases the red-shift by 2400 cm(-1). The remaining factors are due to the change in dispersion interactions. Using an estimate of about 1000 cm(-1) in the dispersion contribution by Houjou et al., we obtained a theoretical opsin shift of 5200 cm(-1) in bR, which is in excellent agreement with the experimental value of 5100 cm(-1). Structural analysis of the PSB binding site revealed the specific interactions that make contributions to the observed opsin shift. The combined QM/MM method used in the present study provides an opportunity to accurately model the photoisomerization and proton transfer reactions in bR.     

A new QM/MM method oriented to the study of ionic liquids

The interest on room temperature ionic liquids has grown in the last decades because of their use as all‐purpose solvent and their low environmental impact. In the present work, a new theoretical procedure is developed to study pure ionic liquids within the framework of the quantum mechanics/molecular mechanics method. Each type of ion (cation or anion) is considered as an independent entity quantum mechanically described that follows a differentiated path in the liquid. The method permits, through an iterative procedure, the full coupling between the polarized charge distribution of the ions and the liquid structure around them. The procedure has been tested with 1‐ethyl‐3‐methylimidazolium tetrafluoroborate. It was found that, similar to non‐polar liquids and as a consequence of the low value of the reaction field, the cation and anion charge distributions are hardly polarized by the rest of molecules in the liquid. Their structure is characterized by an alternance between anion and cation shells as evidenced by the coincidence of the first maximum of the anion–anion and cation–cation radial distribution functions with the first minimum of the anion‐cation. Some degree of stacking between the cations is also found. © 2015 Wiley Periodicals, Inc.     

A QM/MM study of the binding of RAPTA ligands to cathepsin B

We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson–Boltzmann solvent-accessible surface area solvation) has been used to estimate binding affinities. The QM calculations reproduce the antitumour activities of the complexes with a correlation coefficient (r ²) of 0.35–0.86 after a conformational search. The QM/MM-PBSA method gave a better correlation (r ² = 0.59) when the protein was fixed to the crystal structure, but more reasonable ligand structures and absolute binding energies were obtained if the protein was allowed to relax, indicating that the ligands are strained when the protein is kept fixed. In addition, the best correlation (r ² = 0.80) was obtained when only the QM energies were used, which suggests that the MM and continuum solvation energies are not accurate enough to predict the binding of a charged metal complex to a charged protein. Taking into account the protein flexibility by means of MD simulations slightly improves the correlation (r ² = 0.91), but the absolute energies are still too large and the results are sensitive to the details in the calculations, illustrating that it is hard to obtain stable predictions when full flexible protein is included in the calculations.     

Hybrid QM/MM study of thio effects in transphosphorylation reactions

Results of a series of hybrid quantum mechanical/molecular mechanical (QM/MM) activated dynamics simulations of thio effects in the transphosphorylation (methanolysis) of a 2'-ribose, 5'-methyl phosphate-diester under basic conditions are presented. Single and double substitutions in the nonbridging oxygen positions exhibit thio effects in accord with experimental data and show the existence of a stable intermediate. Thio substitution at the 2' and 5' positions resulted in reactions having a single transition state with increased and decreased free energy barriers, respectively, relative to the unsubstituted reaction. In all of the reactions except for the 5' substitution, the rate-limiting step corresponds to exocyclic cleavage. In the 5' substitution reaction, the rate-limiting step corresponds to endocyclic cleavage and shows a considerable reverse thio effect, in accord with experimental observations of phosphates with enhanced leaving groups. Thio substitution at the 3' position results in a mild reverse thio effect that arises from electronic stabilization of the dianionic transition state. The results presented here provide an important step toward the development and application of new hybrid QM/MM methods that, combined with experiment, may provide a detailed picture of the molecular mechanisms of RNA catalysis.     

Solvents effects on the mechanism of cellulose hydrolysis: A QM/MM study

This article reports a combined quantum mechanics/molecular mechanics (QM/MM) investigation on the acid hydrolysis of cellulose in water using two different models, cellobiose and a 40‐unit cellulose chain. The explicitly treated solvent molecules strongly influence the conformations, intramolecular hydrogen bonds, and exoanomeric effects in these models. As these features are largely responsible for the barrier to cellulose hydrolysis, the present QM/MM results for the pathways and reaction intermediates in water are expected to be more realistic than those from a former density functional theory (DFT) study with implicit solvent (CPCM). However, in a qualitative sense, there is reasonable agreement between the DFT/CPCM and QM/MM predictions for the reaction mechanism. Differences arise mainly from specific solute–solvent hydrogen bonds that are only captured by QM/MM and not by DFT/CPCM. © 2015 Wiley Periodicals, Inc.     

Interfacing Q-Chem and CHARMM to perform QM/MM reaction path calculations

A hybrid quantum mechanical/molecular mechanical (QM/MM) potential energy function with Hartree-Fock, density functional theory (DFT), and post-HF (RIMP2, MP2, CCSD) capability has been implemented in the CHARMM and Q-Chem software packages. In addition, we have modified CHARMM and Q-Chem to take advantage of the newly introduced replica path and the nudged elastic band methods, which are powerful techniques for studying reaction pathways in a highly parallel (i.e., parallel/parallel) fashion, with each pathway point being distributed to a different node of a large cluster. To test our implementation, a series of systems were studied and comparisons were made to both full QM calculations and previous QM/MM studies and experiments. For instance, the differences between HF, DFT, MP2, and CCSD QM/MM calculations of H2O...H2O, H2O...Na+, and H2O...Cl- complexes have been explored. Furthermore, the recently implemented polarizable Drude water model was used to make comparisons to the popular TIP3P and TIP4P water models for doing QM/MM calculations. We have also computed the energetic profile of the chorismate mutase catalyzed Claisen rearrangement at various QM/MM levels of theory and have compared the results with previous studies. Our best estimate for the activation energy is 8.20 kcal/mol and for the reaction energy is -23.1 kcal/mol, both calculated at the MP2/6-31+G(d)//MP2/6-31+G(d)/C22 level of theory.     

How does the cAMP-dependent protein kinase catalyze the phosphorylation reaction: an ab initio QM/MM study

We have carried out density functional theory QM/MM calculations on the catalytic subunit of cAMP-dependent protein kinase (PKA). The QM/MM calculations indicate that the phosphorylation reaction catalyzed by PKA is mainly dissociative, and Asp166 serves as the catalytic base to accept the proton delivered by the substrate peptide. Among the key interactions in the active site, the Mg(2+) ions, glycine rich loop, and Lys72 are found to stabilize the transition state through electrostatic interactions. On the other hand, Lys168, Asn171, Asp184, and the conserved waters bound to Mg(2+) ions do not directly contribute to lower the energy barrier of the phosphorylation reaction, and possible roles for these residues are proposed. The QM/MM calculations with different QM/MM partition schemes or different initial structures yield consistent results. In addition, we have carried out 12 ns molecular dynamics simulations on both wild type and K168A mutated PKA, respectively, to demonstrate that the catalytic role of Lys168 is to keep ATP and substrate peptide in the near-attack reactive conformation.     

A comparative QM/MM simulation study of the reaction mechanisms of human and Plasmodium falciparum HG(X)PRTases

QM/MM hybrid potential free-energy simulations are performed to compare the reaction mechanisms of human hypoxanthine guanine phosphoribosyl transferase (HGPRTase) and the corresponding enyzme from Plasmodium falciparum (Pf), hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRTase). These enzymes share 44% of sequence identity but display very different affinities for xanthine. The calculations show that in both enzymes phosphoribosyl transfer proceeds via a dissociative mechanism from an anionic form of the substrate. Nevertheless, there are significant differences in the geometries of critical structures along the reaction paths which it may be possible to exploit for the design of specific inhibitors against the Pf enzyme.     

A versatile AMBER-Gaussian QM/MM interface through PUPIL

The PUPIL package (Program for User Package Interfacing and Linking) originally was developed to interface different programs for multiscale calculations in materials sciences (Torras et al., J Comput Aided Mater Des 2006, 13, 201; Torras et al., Comput Phys Commun 2007, 177, 265). Here we present an extension of PUPIL to computational chemistry by interfacing two widely used computational chemistry programs: AMBER (molecular dynamics) and Gaussian (quantum chemistry). The benefit is to allow the application of the advanced MD techniques available in AMBER to a hybrid QM/MM system in which the forces and energy on the QM part can be computed by any of the methods available in Gaussian. To illustrate, we present two example applications: A MD calculation of alanine dipeptide in explicit water, and a use of the steered MD capabilities in AMBER to calculate the free energy of reaction for the dissociation of Angeli's salt.     

Combined QM/MM study of the mechanism and kinetic isotope effect of the nucleophilic substitution reaction in haloalkane dehalogenase

Combined QM/MM molecular dynamics simulations have been carried out for the dehalogenation reaction of the nucleophilic displacement of dichloroethane catalyzed by haloalkane dehalogenase. The computed chlorine kinetic isotope effects and free energies of activation in the wild-type and the Phe172Trp mutant enzyme are found to be consistent with experiment. In comparison with the uncatalyzed model reaction in water, the enzyme lowers the activation barrier by about 16 kcal/mol. The enormous enzymatic action was attributed to a combination of contributions from a change in the solvation effect and transition state stabilization. The unique features of tryptophan's ability to interact favorably with hydrophobic substrates and to form hydrogen bonds to the leaving group chloride ion at the transition state enable both factors to make significant contributions to the barrier lowering mechanism in the enzyme. This is in contrast to the reference reaction in water, in which hydrogen bonding interactions are weakened at the transition state because of dispersed charge distribution at the transition state relative to that in the reactant and product states.     

A QM/MM Investigation of Thymine Dimer Radical Anion Splitting Catalyzed by DNA Photolyase

On the mend : The repair reaction of the thymine dimer by DNA photolyase (see picture) is studied by hybrid quantum mechanical/molecular mechanical dynamics simulations based on the X‐ray structure of the enzyme–DNA complex. The dynamics of splitting of the thymine dimer radical anion within the DNA photolyase active site is characterized. The model includes the protein environment.