Insight into the redox partner interaction mechanism in cytochrome P450BM-3 using molecular dynamics simulations

Verma, Rajni, Schwaneberg, Ulrich and Roccatano, Danilo (2014) Insight into the redox partner interaction mechanism in cytochrome P450BM-3 using molecular dynamics simulations. Biopolymers, 101 (3). pp. 197-209. ISSN 0006-3525

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Flavocytochrome P450BM-3 is a soluble bacterial reductase composed of two flavin (FAD/FMN) and one HEME domains. In this article, we have performed molecular dynamics simulations on both the isolated FMN and HEME domains and their crystallographic complex, with the aim to study their binding modes and to garner insight into the interdomain electron transfer (ET) mechanism. The results evidenced an interdomain conformational rearrangement that reduces the average distance between the FMN and HEME cofactors from 1.81 nm, in the crystal structure, to an average value of 1.41 ± 0.09 nm along the simulation. This modification is in agreement with previously proposed hypotheses suggesting that the crystallographic FMN/HEME complex is not in the optimal arrangement for favorable ET rate under physiological conditions. The calculation of the transfer rate along the simulation, using the Pathways Path method, demonstrated the occurrence of seven ET pathways between the two redox centers, with three of them providing ET rates (KET ) comparable with the experimental one. The sampled ET pathways comprise the amino acids N319, L322, F390, K391, P392, F393, A399, C400, and Q403 of the HEME domain and M490 of the FMN domain. The values of KET closer to the experiment were found along the pathways FMN(C7) → F390 → K391 → P392 → HEME(Fe) and FMN(C8) → M490 → F393 → HEME(Fe). Finally, the analysis of the collective modes of the protein complex evidences a clear correlation of the first two essential modes with the activation of the most effective ET pathways along the trajectory. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 197-209, 2014.

Keywords:cytochrome P450 monooxygenase, interdomain electron transfer, NotOAChecked
Subjects:C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
Divisions:College of Science
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ID Code:19518
Deposited On:09 Nov 2015 09:08

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