| 1. |
- Lecerof, David, et al.
(författare)
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Metal binding to Bacillus subtilis ferrochelatase and interaction between metal sites.
- 2003
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Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 1432-1327 .- 0949-8257. ; 8:4, s. 452-458
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Tidskriftsartikel (refereegranskat)abstract
- Ferrochelatase, the terminal enzyme in heme biosynthesis, catalyses metal insertion into protoporphyrin IX. The location of the metal binding site with respect to the bound porphyrin substrate and the mode of metal binding are of central importance for understanding the mechanism of porphyrin metallation. In this work we demonstrate that Zn2+, which is commonly used as substrate in assays of the ferrochelatase reaction, and Cd2+, an inhibitor of the enzyme, bind to the invariant amino acids His183 and Glu264 and water molecules, all located within the porphyrin binding cleft. On the other hand, Mg2+, which has been shown to bind close to the surface at 7 Å from His183, was largely absent from its site. Activity measurements demonstrate that Mg2+ has a stimulatory effect on the enzyme, lowering KM for Zn2+ from 55 to 24 µM. Changing one of the Mg2+ binding residues, Glu272, to serine abolishes the effect of Mg2+. It is proposed that prior to metal insertion the metal may form a sitting-atop (SAT) complex with the invariant His-Glu couple and the porphyrin. Metal binding to the Mg2+ site may stimulate metal release from the protein ligands and its insertion into the porphyrin.
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| 2. |
- Karlström, Gunnar, et al.
(författare)
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MOLCAS : a program package for computational chemistry
- 2003
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Ingår i: Computational materials science. - 0927-0256 .- 1879-0801. ; 28:2, s. 222-239
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Tidskriftsartikel (refereegranskat)abstract
- The program system MOLCAS is a package for calculations of electronic and structural properties of molecular systems in gas, liquid, or solid phase. It contains a number of modern quantum chemical methods for studies of the electronic structure in ground and excited electronic states. A macromolecular environment can be modeled by a combination of quantum chemistry and molecular mechanics. It is further possible to describe a crystalline material using model potentials. Solvent effects can be treated using continuum models or by combining quantum chemical calculations with molecular dynamics or Monte-Carlo simulations. MOLCAS is especially adapted to treat systems with a complex electronic structure, where the simplest quantum chemical models do not work. These features together with the inclusion of relativistic effects makes it possible to treat with good accuracy systems including atoms from the entire periodic system. MOLCAS has effective methods for geometry optimization of equilibria, transition states, conical intersections, etc. This facilitates studies of excited state energy surfaces, spectroscopy, and photochemical processes.
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| 3. |
- Lindh, Roland, et al.
(författare)
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On the significance of the trigger reaction in the action of the calicheamicin γI 1 anti-cancer drug
- 1997
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Ingår i: Theoretical Chemistry Accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 97:1, s. 203-210
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Tidskriftsartikel (refereegranskat)abstract
- The significance of the so-called trigger reaction in the reaction mechanism of the calicheamicin γI 1 anti-cancer drug has been studied with ab initio quantum chemical methods. The structures of four fragments of calicheamicin γI 1, consisting of either 39 or 41 atoms, have been fully optimized using the Becke-Perdew86 density functional method and the 6-31G* basis sets. The four structures constitute members of an isodesmic reaction for which the reaction energy is a direct measure of the change in activation energy of the Bergman reaction, caused by the structural rearrangements of the preceding trigger reaction. This difference in activation energy has been calculated with density functional theory, using the exchange-correlation functional mentioned above, and with second-order Møller-Plesset perturbation theory (MP2), employing an ANO-type basis set. In both cases a value of 12 kcal/ mol is obtained. The study firmly supports the hypothesis that the significance of the trigger reaction is to saturate a double bond in the vicinity of the enediyne group, which counteracts the formation of the biradical state of the drug. The MP2 computations became feasible by a novel implementation of an integral-direct, distributed-data, parallel MP2 algorithm.
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| 4. |
- Rydberg, Patrik, et al.
(författare)
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General transition-state force field for cytochrome p450 Hydroxylation
- 2007
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 3:5, s. 1765-1773
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Tidskriftsartikel (refereegranskat)abstract
- We have developed force-field parameters for the hydrogen-abstraction transition state of aliphatic hydroxylation by cytochrome P450 using the Q2MM approach. The parametrization is based on quantum chemical (B3LYP) transition-state structures and Hessian matrices for 24 diverse substrate models (14 in the training set and 10 in the test set). The force field is intended to be applicable to any druglike molecule by the use of the general Amber force field (GAFF) for the substrates. The parameters reproduce the geometries within 0.1 angstrom and 1.2 degrees for bond lengths and angles, respectively, with no significant differences between the training and test sets. The Hessian matrix is also well reproduced with a correlation coefficient of 0.99. The parametrization is performed by the ideal iterative approach of Norrby and Liljefors, which we have implemented for the Amber software.
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| 5. |
- Rydberg, Patrik, et al.
(författare)
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Transition-State Docking of Flunitrazepam and Progesterone in Cytochrome P450
- 2008
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Ingår i: J.Chem.Theory Comput.. - : American Chemical Society (ACS). ; 4, s. 673-681
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a method to dock a transition-state structure into the active site of an enzyme. Such an approach is more discriminative than standard docking when looking for substrates of an enzyme, because a transition state has more sterical restrictions than a nonreactive state. We use an accurate and tailored force field for the transition-state for the hydroxylation reaction in cytochrome P450, obtained with the Q2MM method. We apply this method to the docking of two drugs, progesterone and flunitrazepam, to the active sites of two human cytochromes P450, 2C9 and 3A4. We obtain a qualitative agreement compared to experiments, both for hydrogen atoms bound to the same carbon atom (for which the force-field energies are directly comparable) and for general sites on the drug molecules, if the method is combined with an estimate of the intrinsic reactivity of the various sites. However, the method does not rank all the sites correctly. It is not significantly improved if the proteins are allowed to relax locally or if it is combined with the MM/PBSA approach, which fully accounts for the protein flexibility and explicitly treats solvation and entropy effects. On the other hand our method performs better than standard docking with the GOLD software or predictions of metabolic sites with the MetaSite software.
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| 6. |
- Sigfridsson, Emma, et al.
(författare)
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On the significance of hydrogen bonds for the discrimination between CO and O2 by myoglobin
- 1999
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Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 0949-8257 .- 1432-1327. ; 4:1, s. 99-110
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Tidskriftsartikel (refereegranskat)abstract
- Quantum chemical geometry optimisations have been performed on realistic models of the active site of myoglobin using density functional methods. The energy of the hydrogen bond between the distal histidine residue and CO or O2 has been estimated to be 8 kJ/mol and 32 kJ/mol, respectively. This 24 k J/mol energy difference accounts for most of the discrimination between CO and O2 by myoglobin (about 17 kJ/mol). Thus, steric effects seem to be of minor importance for this discrimination. The Fe-C and C-O vibrational frequencies of CO-myoglobin have also been studied and the results indicate that CO forms hydrogen bonds to either the distal histidine residue or a water molecule during normal conditions. We have made several attempts to optimize structures with the deprotonated nitrogen atom of histidine directed towards CO. However, all such structures lead to unfavourable interactions between the histidine and CO, and to ν(CO) frequencies higher than those observed experimentally.
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| 7. |
- Söderhjelm, Pär, et al.
(författare)
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Accuracy of distributed multipoles and polarizabilities: Comparison between the LoProp and MpProp models
- 2007
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 1096-987X .- 0192-8651. ; 28:6, s. 1083-1090
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Tidskriftsartikel (refereegranskat)abstract
- Localized multipole moments up to the fifth moment as well as localized dipole polarizabilities are calculated with the MpProp and the newly developed LoProp methods for a total of 20 molecules, predominantly derived from amino acids. A comparison of electrostatic potentials calculated from the multipole expansion obtained by the two methods with ab initio results shows that both methods reproduce the electrostatic interaction with an elementary charge with a mean absolute error of similar to 1.5 kJ/mol at contact distance and less than 0.1 kJ/mol at distances 2 angstrom further out when terms up to the octupole moments are included. The polarizabilities are tested with homogenous electric fields and are-found to have similar accuracy. The MpProp method gives better multipole moments unless diffuse basis sets are used, whereas LoProp gives better polarizabilities. (C) 2007 Wiley Periodicals, Inc.
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| 8. |
- Söderhjelm, Pär, et al.
(författare)
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Calculation of Protein-Ligand Interaction Energies by a Fragmentation Approach Combining High-Level Quantum Chemistry with Classical Many-Body Effects
- 2009
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:32, s. 11085-11094
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a method to estimate accurate interaction energies between a full protein and a bound ligand. It is based oil the recently proposed PMISP (polarizable multipole interaction with supermolecular pairs) method (Soderhjelm, P.; Ryde, U. J. Phys. Chem. A 2009, 113. 617), which treats electrostatic interaction by multipoles up to quadrupoles, induction by anisotropic polarizabilities, and nonclassical interactions by explicit quantum mechanical (QM) calculations, using a fragmentation approach. For a whole protein, electrostatics and induction are treated the same way, but for the nonclassical interactions, a Lennard-Jones term from a standard molecular mechanics (MM) force field (e.g., Amber) is used outside a certain distance from the ligand (4-7 angstrom). This QM/MM variant of the PMISP method is carefully tested by varying this distance. Several approximations related to the classical interactions are also evaluated. It is found that one can speed up the calculation by using density functional theory to compute multipoles and polarizabilities but that a proper treatment of polarization is important. As a demonstration of the method, the interaction energies of two ligands bound to avidin are calculated at the MP2/aug-cc-pVTZ level, with an expected relative error of 1-2%.
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| 9. |
- Verteramo, Maria Luisa, et al.
(författare)
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Interplay of halogen bonding and solvation in protein-ligand binding
- 2024
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Ingår i: iScience. - 2589-0042. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Halogen bonding is increasingly utilized in efforts to achieve high affinity and selectivity of molecules designed to bind proteins, making it paramount to understand the relationship between structure, dynamics, and thermodynamic driving forces. We present a detailed analysis addressing this problem using a series of protein-ligand complexes involving single halogen substitutions - F, Cl, Br, and I - and nearly identical structures. Isothermal titration calorimetry reveals an increasingly favorable binding enthalpy from F to I that correlates with the halogen size and σ-hole electropositive character, but is partially counteracted by unfavorable entropy, which is constant from F to Cl and Br, but worse for I. Consequently, the binding free energy is roughly equal for Cl, Br, and I. QM and solvation-free-energy calculations reflect an intricate balance between halogen bonding, hydrogen bonds, and solvation. These advances have the potential to aid future drug design initiatives involving halogenated compounds.
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| 10. |
- Andrejic, Milica, et al.
(författare)
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Coupled-Cluster Interaction Energies for 200-Atom Host-Guest Systems
- 2014
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Ingår i: ChemPhysChem. - : Wiley. - 1439-7641 .- 1439-4235. ; 15:15, s. 3270-3281
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a method to calculate interaction energies of large systems (such as host-guest or even protein-ligand systems) at the local coupled-cluster with singles, doubles, and perturbative triples level, and with extrapolation to the limit of a complete basis set. The method is based on the polarizable multipole interactions with supermolecular pairs molecular fractionation approach, which combines a pairwise quantum-mechanical evaluation of the short-range interactions with a polarizable multipole treatment of many-body effects. The method is tested for nine guest molecules binding to an octa-acid host (in total 198-207 atoms), as part of the SAMPL4 blind challenge. From the test calculations, the accuracy of the approach is found to be 10 kJ mol(-1) or better. Comparison with dispersion-corrected density functional theory reveals that the latter underestimates the dispersion contribution for this type of system, which leads to a difference in the ranking of the ligands.
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