Journal article
Kinetics of O2 Entry and Exit in Monomeric Sarcosine Oxidase via Markovian Milestoning Molecular Dynamics
Journal of chemical theory and computation, v 12(6), pp 2964-2972
14 Jun 2016
PMID: 27168219
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The flavoenzyme monomeric sarcosine oxidase (MSOX) catalyzes a complex set of reactions currently lacking a consensus mechanism. A key question that arises in weighing competing mechanistic models of MSOX function is to what extent ingress of O2 from the solvent (and its egress after an unsuccessful oxidation attempt) limits the overall catalytic rate. To address this question, we have applied to the MSOX/O2 system the relatively new simulation method of Markovian milestoning molecular dynamics simulations, which, as we recently showed [ Yu et al. J. Am. Chem. Soc. 2015 , 137 , 3041 ], accurately predicted the entry and exit kinetics of CO in myoglobin. We show that the mechanism of O2 entry and exit, in terms of which possible solvent-to-active-site channels contribute to the flow of O2, is sensitive to the presence of the substrate-mimicking competitive inhibitor 2-furoate in the substrate site. The second-order O2 entry rate constants were computed to be 8.1 × 10(6) and 3.1 × 10(6) M(-1) s(-1) for bound and apo MSOX, respectively, both of which moderately exceed the experimentally determined second-order rate constant of (2.83 ± 0.07) × 10(5) M(-1) s(-1) for flavin oxidation by O2 in MSOX. This suggests that the rate of flavin oxidation by O2 is likely not strongly limited by diffusion from the solvent to the active site. The first-order exit rate constants were computed to be 10(7) s(-1) and 7.2 × 10(6) s(-1) for the apo and bound states, respectively. The predicted faster entry and slower exit of O2 for the bound state indicate a longer residence time within MSOX, increasing the likelihood of collisions with the flavin isoalloxazine ring, a step required for reduction of molecular O2 and subsequent reoxidation of the flavin. This is also indirectly supported by previous experimental evidence favoring the so-called modified ping-pong mechanism, the distinguishing feature of which is an intermediate complex involving O2, the flavin, and the oxidized substrate simultaneously in the cavity. These findings demonstrate the utility of the Markovian milestoning approach in contributing new understanding of complicated enyzmatic function.
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Details
- Title
- Kinetics of O2 Entry and Exit in Monomeric Sarcosine Oxidase via Markovian Milestoning Molecular Dynamics
- Creators
- Anthony Bucci - Department of Chemical and Biological Engineering, Drexel University , Philadelphia, Pennsylvania 19104, United StatesTang-Qing Yu - Courant Institute of Mathematical Sciences, New York University , New York, New York 10012, United StatesEric Vanden-Eijnden - Courant Institute of Mathematical Sciences, New York University , New York, New York 10012, United StatesCameron F Abrams - Department of Chemical and Biological Engineering, Drexel University , Philadelphia, Pennsylvania 19104, United States
- Publication Details
- Journal of chemical theory and computation, v 12(6), pp 2964-2972
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- R01 GM100472 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000378016000043
- Scopus ID
- 2-s2.0-84974815591
- Other Identifier
- 991014877949804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Physical
- Physics, Atomic, Molecular & Chemical