| 1. |
- Srnec, Martin, et al.
(författare)
-
Reaction Mechanism of Manganese Superoxide Dismutase Studied by Combined Quantum and Molecular Mechanical Calculations and Multiconfigurational Methods.
- 2009
-
Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:17, s. 6074-6086
-
Tidskriftsartikel (refereegranskat)abstract
- Manganese superoxide dismutases (MnSODs) are enzymes that convert two molecules of the poisonous superoxide radical into molecular oxygen and hydrogen peroxide. During the reaction, the manganese ion cycles between the Mn(2+) and Mn(3+) oxidation states and accomplishes its enzymatic action in two half-cycles (corresponding to the oxidation and reduction of O(2)(*-)). Despite many experimental and theoretical studies dealing with SODs, including quantum chemical active-site-model studies of numerous variants of the reaction mechanisms, several details of MnSOD enzymatic action are still unclear. In this study, we have modeled and compared four reaction pathways (one associative, one dissociative, and two second-sphere) in a protein environment using the QM/MM approach (combined quantum and molecular mechanics calculations) at the density functional theory level. The results were complemented by CASSCF/CASPT2/MM single-point energy calculations for the most plausible models to account properly for the multireference character of the various spin multiplets. The results indicate that the oxidation of O(2)(*-) to O(2) most likely occurs by an associative mechanism following a two-state (quartet-octet) reaction profile. The barrier height is estimated to be less than 25 kJ.mol(-1). On the other hand, the conversion of O(2)(*-) to H(2)O(2) is likely to take place by a second-sphere mechanism, that is, without direct coordination of the superoxide radical to the manganese center. The reaction pathway involves the conical intersection of two quintet states, giving rise to an activation barrier of approximately 60 kJ.mol(-1). The calculations also indicate that the associative mechanism can represent a competitive pathway in the second half-reaction with the overall activation barrier being only slightly higher than the activation barrier in the second-sphere mechanism. The activation barriers along the proposed reaction pathways are in very good agreement with the experimentally observed reaction rates of SODs (k(cat) approximately 10(4)-10(5) s(-1)).
|
|
| 2. |
- Söderhjelm, Pär, et al.
(författare)
-
Calculation of Protein-Ligand Interaction Energies by a Fragmentation Approach Combining High-Level Quantum Chemistry with Classical Many-Body Effects
- 2009
-
Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:32, s. 11085-11094
-
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%.
|
|
