Predicting enzyme-substrate specificity with QM/MM methods: a case study of the stereospecificity of (D)-glucarate dehydratase.
Ontology highlight
ABSTRACT:
SUBMITTER: Tian B
PROVIDER: S-EPMC3964877 | biostudies-literature | 2013 Aug
REPOSITORIES: biostudies-literature
Publications
Predicting enzyme-substrate specificity with QM/MM methods: a case study of the stereospecificity of (D)-glucarate dehydratase.
Tian Boxue B Wallrapp Frank F Kalyanaraman Chakrapani C Zhao Suwen S Eriksson Leif A LA Jacobson Matthew P MP
Biochemistry 20130809 33
The stereospecificity of d-glucarate dehydratase (GlucD) is explored by QM/MM calculations. Both the substrate binding and the chemical steps of GlucD contribute to substrate specificity. Although the identification of transition states remains computationally intensive, we suggest that QM/MM computations on ground states or intermediates can capture aspects of specificity that cannot be obtained using docking or molecular mechanics methods. ...[more]
Similar Datasets
Project description:Choline oxidase catalyzes oxidation of choline into glycine betaine through a two-step reaction pathway employing flavin as the cofactor. On the light of kinetic studies, it is proposed that a hydride ion is transferred from α-carbon of choline/hydrated-betaine aldehyde to the N5 position of flavin in the rate-determining step, which is preceded by deprotonation of hydroxyl group of choline/hydrated-betaine aldehyde to one of the possible basic side chains. Using the crystal structure of glycine betaine-choline oxidase complex, we formulated two computational systems to study the hydride-transfer mechanism including main active-site amino acid side chains, flavin cofactor, and choline as a model system. The first system used pure density functional theory calculations, whereas the second approach used a hybrid ONIOM approach consisting of density functional and molecular mechanics calculations. We were able to formulate in silico model active sites to study the hydride-transfer steps by utilizing noncovalent chemical interactions between choline/betaine aldehyde and active-site amino acid chains using an atomistic approach. We evaluated and compared the geometries and energetics of hydride-transfer process using two different systems. We highlighted chemical interactions and studied the effect of protonation state of an active-site histidine base on the energetics of transfer. Furthermore, we evaluated energetics of the second hydride-transfer process as well as hydration of betaine aldehyde.
| S-EPMC6643517 | biostudies-literature
Project description:Using a structure generated by induced fit modeling of the protein-ligand complex, the reaction path for hydrogen atom abstraction in P450 BM3 is studied by means of mixed QM/MM methods to determine the structures and energetics along the reaction path. The IFD structure is suitable for hydrogen atom abstraction at the ?-1 position. The electronic structures obtained are similar to those observed in P450 cam. We show that the barrier for the hydrogen abstraction step from QM/MM modeling is 13.3 kcal/mol in quartet and 15.6 kcal/mol in doublet. Although there is some strain energy present in the ligand, the activation barrier is not dramatically affected. A crystal water molecule, HOH502, plays a role as catalyst and decreases the activation barrier by about 2 kcal/mol and reaction energy by about 3-4 kcal/mol. In order to achieve reactive chemistry at the remaining experimentally observed positions in the hydrocarbon tail of the ligand, other structures would have to be utilized as a starting point for the reaction. Finally, the present results still leave open the question of whether DFT methods provide an accurate computation of the barrier height in the P450 hydrogen atom abstraction reaction.
| S-EPMC2757081 | biostudies-literature
Project description:Mixed quantum mechanics/molecular mechanics (QM/MM) methods offer a valuable computational tool for understanding the electron transfer pathway in protein-substrate interactions and protein-protein complexes. These hybrid methods are capable of solving the Schrödinger equation on a small subset of the protein, the quantum region, describing its electronic structure under the polarization effects of the remainder of the protein. By selectively turning on and off different residues in the quantum region, we are able to obtain the electron pathway for short- and large-range interactions. Here, we summarize recent studies involving the protein-substrate interaction in cytochrome P450 camphor, ascorbate peroxidase and cytochrome c peroxidase, and propose a novel approach for the long-range protein-protein electron transfer. The results on ascorbate peroxidase and cytochrome c peroxidase reveal the importance of the propionate groups in the electron transfer pathway. The long-range protein-protein electron transfer has been studied on the cytochrome c peroxidase-cytochrome c complex. The results indicate the importance of Phe82 and Cys81 on cytochrome c, and of Asn196, Ala194, Ala176 and His175 on cytochrome c peroxidase.
| S-EPMC2706105 | biostudies-literature
Project description:The catalytic mechanism of the decarboxylation of 5-carboxyvanillate by LigW producing vanillic acid has been studied by using QM cluster and hybrid QM/MM methodologies. In the QM cluster model, the environment of a small QM model is treated with a bulky potential while two QM/MM models studies include partial and full protein with and without explicitly treated water solvent. The studied reaction involves two sequential steps: the protonation of the carbon of the 5-carboxy-vanillate substrate and the decarboxylation of the intermediate from which results deprotonated vanillic acid as product. The structures and energetics obtained by using three structural models and two density functionals are quite consistent to each other. This indicates that the small QM cluster model of the presently considered enzymatic reaction is appropriate enough and the reaction is mainly influenced by the active site.
| S-EPMC6031855 | biostudies-literature
Project description:Multidrug-resistant organisms contain antibiotic-modifying enzymes that facilitate resistance to a variety of antimicrobial compounds. Particularly, the fosfomycin (FOF) drug can be structurally modified by several FOF-modifying enzymes before it reaches the biological target. Among them, FosB is an enzyme that utilizes l-cysteine or bacillithiol in the presence of a divalent metal to open the epoxide ring of FOF and, consequently, inactivate the drug. Here, we have used hybrid quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations to explore the mechanism of the reaction involving FosB and FOF. The calculated free-energy profiles show that the cost to open the epoxide ring of FOF at the C2 atom is ∼3.0 kcal/mol higher than that at the C1 atom. Besides, our QM/MM MD results revealed the critical role of conformation change of Cys9 and Asn50 to release the drug from the active site. Overall, the present study provides insights into the mechanism of FOF-resistant proteins.
| S-EPMC8154160 | biostudies-literature
Project description:To validate a method for predicting the binding affinities of FabI inhibitors, three implicit solvent methods, MM-PBSA, MM-GBSA, and QM/MM-GBSA were carefully compared using 16 benzimidazole inhibitors in complex with Francisella tularensis FabI. The data suggests that the prediction results are sensitive to radii sets, GB methods, QM Hamiltonians, sampling protocols, and simulation length, if only one simulation trajectory is used for each ligand. In this case, QM/MM-GBSA using 6 ns MD simulation trajectories together with GB(neck2) , PM3, and the mbondi2 radii set, generate the closest agreement with experimental values (r(2) = 0.88). However, if the three implicit solvent methods are averaged from six 1 ns MD simulations for each ligand (called "multiple independent sampling"), the prediction results are relatively insensitive to all the tested parameters. Moreover, MM/GBSA together with GB(HCT) and mbondi, using 600 frames extracted evenly from six 0.25 ns MD simulations, can also provide accurate prediction to experimental values (r(2) = 0.84). Therefore, the multiple independent sampling method can be more efficient than a single, long simulation method. Since future scaffold expansions may significantly change the benzimidazole's physiochemical properties (charges, etc.) and possibly binding modes, which may affect the sensitivities of various parameters, the relatively insensitive "multiple independent sampling method" may avoid the need of an entirely new validation study. Moreover, due to large fluctuating entropy values, (QM/)MM-P(G)BSA were limited to inhibitors' relative affinity prediction, but not the absolute affinity. The developed protocol will support an ongoing benzimidazole lead optimization program.
| S-EPMC4688044 | biostudies-literature
Project description:We have made a systematic combined quantum mechanical and molecular mechanical (QM/MM) investigation of possible structures of the N2 bound state of nitrogenase. We assume that N2 is immediately protonated to a N2H2 state, thereby avoiding the problem of determining the position of the protons in the cluster. We have systematically studied both end-on and side-on structures, as well as both HNNH and NNH2 states. Our results indicate that the binding of N2H2 is determined more by interactions and steric clashes with the surrounding protein than by the intrinsic preferences of the ligand and the cluster. The best binding mode with both the TPSS and B3LYP density-functional theory methods has trans-HNNH terminally bound to Fe2. It is stabilised by stacking of the substrate with His-195 and Ser-278. However, several other structures come rather close in energy (within 3-35 kJ/mol) at least in some calculations: The corresponding cis-HNNH structure terminally bound to Fe2 is second best with B3LYP. A structure with HNNH2 terminally bound to Fe6 is second most stable with TPSS (where the third proton is transferred to the substrate from the homocitrate ligand). Structures with trans-HNNH, bound to Fe4 or Fe6, or cis-HNNH bound to Fe6 are also rather stable. Finally, with the TPSS functional, a structure with cis-HNNH side-on binding to the Fe3-Fe4-Fe5-Fe7 face of the cluster is also rather low in energy, but all side-on structures are strongly disfavoured by the B3LYP method.
| S-EPMC7186253 | biostudies-literature
Project description:Hybrid quantum mechanical-molecular mechanical (QM/MM) simulations are widely used in studies of enzymatic catalysis. Until recently, it has been cost prohibitive to determine the asymptotic limit of key energetic and structural properties with respect to increasingly large QM regions. Leveraging recent advances in electronic structure efficiency and accuracy, we investigate catalytic properties in catechol O-methyltransferase, a prototypical methyltransferase critical to human health. Using QM regions ranging in size from reactants-only (64 atoms) to nearly one-third of the entire protein (940 atoms), we show that properties such as the activation energy approach within chemical accuracy of the large-QM asymptotic limits rather slowly, requiring approximately 500-600 atoms if the QM residues are chosen simply by distance from the substrate. This slow approach to asymptotic limit is due to charge transfer from protein residues to the reacting substrates. Our large QM/MM calculations enable identification of charge separation for fragments in the transition state as a key component of enzymatic methyl transfer rate enhancement. We introduce charge shift analysis that reveals the minimum number of protein residues (approximately 11-16 residues or 200-300 atoms for COMT) needed for quantitative agreement with large-QM simulations. The identified residues are not those that would be typically selected using criteria such as chemical intuition or proximity. These results provide a recipe for a more careful determination of QM region sizes in future QM/MM studies of enzymes.
| S-EPMC5108028 | biostudies-literature
Project description:We examine methods to reweight classical molecular mechanics solvation calculations to more expensive QM/MM energy functions. We first consider the solvation free energy difference between ethane and methanol in a QM/MM Hamiltonian from configurations generated in a cheaper MM potential. The solute molecules in the QM/MM Hamiltonian are treated with B3LYP/6-31G*, and the solvent water molecules are treated classically. The free energy difference in the QM/MM Hamiltonian is estimated using Boltzmann reweighting with both the non-Boltzmann Bennett method (NBB) and the multistate Bennett acceptance ratio (MBAR), and the variance of each method is directly compared for an identical data set. For this system, MBAR-derived methods are found to produce smaller overall uncertainties than NBB-based methods. Additionally, we show that to reduce the variance in the overall free energy difference estimate in this system for a fixed amount of QM/MM calculations, the energy re-evaluations in the Boltzmann reweighting step should be concentrated on the physical MM states with the highest overlap to the QM/MM states, rather than allocated equally over all sampled MM states. We also show that reallocating the QM/MM re-evaluations can be used to diagnose poor overlap between the sampled and target state. The solvation free energies for molecules in the SAMPL4 solvation data set are also calculated in the QM/MM Hamiltonian with NBB and MBAR, and the variances are marginally smaller for MBAR. Overall, NBB and MBAR produce similar variances for systems with poor sampling efficiency, and MBAR provides smaller variances than NBB in systems with high sampling efficiency. Both NBB and MBAR converge to identical solvation free energy estimates in the QM/MM Hamiltonian, and the RMSD to experimental values for molecules in the SAMPL4 solvation data set decreases by approximately 28% when switching from the MM Hamiltonian to the QM/MM Hamiltonian.
| S-EPMC6497519 | biostudies-literature
Project description:We report a Quantum mechanics/Molecular Mechanics-Poisson-Boltzmann/ Surface Area (QM/MM-PB/SA) method to calculate the binding free energy of c-Abl human tyrosine kinase by combining the QM and MM principles where the ligand is treated quantum mechanically and the rest of the receptor by classical molecular mechanics. To study the role of entropy and the flexibility of the protein ligand complex in a solvated environment, molecular dynamics calculations are performed using a hybrid QM/MM approach. This work shows that the results of the QM/MM approach are strongly correlated with the binding affinity. The QM/MM interaction energy in our reported study confirms the importance of electronic and polarization contributions, which are often neglected in classical MM-PB/SA calculations. Moreover, a comparison of semi-empirical methods like DFTB-SCC, PM3, MNDO, MNDO-PDDG, and PDDG-PM3 is also performed. The results of the study show that the implementation of a DFTB-SCC semi-empirical Hamiltonian that is derived from DFT gives better results than other methods. We have performed such studies using the AMBER molecular dynamic package for the first time. The calculated binding free energy is also in agreement with the experimentally determined binding affinity for c-Abl tyrosine kinase complex with Imatinib.Electronic supplementary material The online version of this article (doi:10.1007/s10867-010-9199-z) contains supplementary material, which is available to authorized users.
| S-EPMC3006460 | biostudies-literature