Theoretical Study of the Enzymatic Sulfoxidation Reaction by Peroxidases.

MARCELO PUIATTI, D. MARIANO A. VERA, ALICIA B. PEÑÉÑORY AND ADRIANA B. PIERINI

Los Cocos, Córdoba, Argentina

Congreso; 9th Latin American Conference on Physical Organic Chemistry; 2007

Latin American Committee of Physical Organic Chemistry

The enzymatic oxidation of sulfides can be achieved by peroxidases, such as HRP, CiP and CPO. These enantioselective oxidations, valuable in asymmetric synthesis can take place by two different pathways: direct oxygen transfer and oxygen re-bound mechanism (Scheme 1), both involving the initial formation of the iron(IV)-oxo porphyrin radical cation (Compound I). The so-called oxygen-rebound mechanism (paths Band C, Scheme 1), is triggered by electron transfer (ET) from the sulfide to Compound I, with the generation of the sulfide radical cation intermediate. Experimental results showed that HRP and CiP react by the ET pathway, while CPO follows a direct oxygen transfer.The favored pathway depends both on the structure and the oxidation potential of the substrate and on the enzyme.1,2This study focus on the sulfoxidation reaction, mainly on the structure of the Michaellis complex for each possible path, the polarization exerted by the enzyme on the sulfides, and how their donor capabilities are affected. The methodology combines tools from classical Molecular Dynamics (MD) and ab initio Quantum Mechanics (QM). The enzymes studied are the HRP and CPO, using the AMBER 98 force field extended to describe the protoporphyrin system and the susbstrate on the basis of parameters derived from DFT calculations of the active site (at the B3LYP/LACVP level).3 The sulfides chosen for this work were thioanisole and the cinamyl derivatives, previously studied by experimental methods.2The docking and MD simulations provided suitable structural models for productive Michaelis complexes for thioanisole and cynamyl derivatives. The thioanisole / enzyme Compound I adduct has found to be pro R in the case of the HRP in good agreement with the stereochemistry observed in the experimental studies. Two different sets of geometries arisen from the classical models were studied by means of QM calculations. One of these models revealed an important degree of polarization on the sulfide reflected both in the charge distribution and the appearance of spin density on the sulfide, which would lead to a path compatible with the ET mechanism in the case of the HRP. 1,2This study focus on the sulfoxidation reaction, mainly on the structure of the Michaellis complex for each possible path, the polarization exerted by the enzyme on the sulfides, and how their donor capabilities are affected. The methodology combines tools from classical Molecular Dynamics (MD) and ab initio Quantum Mechanics (QM). The enzymes studied are the HRP and CPO, using the AMBER 98 force field extended to describe the protoporphyrin system and the susbstrate on the basis of parameters derived from DFT calculations of the active site (at the B3LYP/LACVP level).3 The sulfides chosen for this work were thioanisole and the cinamyl derivatives, previously studied by experimental methods.2The docking and MD simulations provided suitable structural models for productive Michaelis complexes for thioanisole and cynamyl derivatives. The thioanisole / enzyme Compound I adduct has found to be pro R in the case of the HRP in good agreement with the stereochemistry observed in the experimental studies. Two different sets of geometries arisen from the classical models were studied by means of QM calculations. One of these models revealed an important degree of polarization on the sulfide reflected both in the charge distribution and the appearance of spin density on the sulfide, which would lead to a path compatible with the ET mechanism in the case of the HRP.