Mapping protein electron transfer pathways with QM/MM methods

Abstract

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.

Mapping the Long-Range Electron Transfer Route in Ligninolytic Peroxidases

“…Numbering above the residues indicates the exposed tryptophan (W164/W171) and the two additional residues (F198/F205 and W244/W251) identified by QM/MM e-pathway 27,28 in P. eryngii VP/P. chrysosporium LiP.…”

“…Illustration of QM/MM e-pathway procedure (that does not presume to represent any result). 27 The strategy consists of identifying the residue that hosts the spin density in a QM/MM calculation (step 1), where only the residues potentially involved in the transfer are placed in the QM region (in orange) whereas donor and acceptor are frozen in the MM region (in green). This residue is then subtracted from the QM region in the following calculations (steps 2 and 3) and the process is iterated until localizing a complete e-pathway (connecting donor and acceptor).…”

“…For example, the module PATHWAYS, from the software HARLEM, 26 identifies the residues with higher probability to act as electron carriers using a geometrical analysis and empirical tunneling factors. In this study, we use an intermediate approach based on a mixed quantum mechanics and molecular mechanics (QM/MM) method, the QM/MM e-pathway, 27, 28 5 providing a semi-quantitative ranking of the residues' electron affinity. This approach has been recently used to identify the LRET route from an exposed tryptophan in a dye-decolorizing peroxidase, a member of a different superfamily also oxidizing lignin-derived products.…”

“…LRET was characterized by the QM/MM e-pathway method, 27 a technique that ranks a set of specified residues by its tendency to host the radical during the electron transfer process (Figure 1). Figure 1.…”

Introduction. Biomolecular simulation

“…This enzyme reaction involves quantum tunnelling, an area that is attracting considerable debate (Allemann et al 2006;Klinman 2006;Sutcliffe et al 2006;Wang et al 2006), a debate in which biomolecular simulation has a crucial role to play (Hammes-Schiffer & Watney 2006; Masgrau et al 2006;Olsson et al 2006). In this Interface Focus, Guallar & Wallrapp (2008) demonstrate a different type of application of QM/MM methods, namely a QM/MM approach to finding electron transfer pathways in proteins. They describe investigations of protein-substrate interactions in cytochrome P450cam, ascorbate peroxidase and cytochrome c peroxidase, and propose a new approach for studying long range electron transfer between proteins, applied here to the cytochrome c peroxidasecytochrome c complex.…”