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Analysis of water channels by molecular dynamics simulation of heterotetrameric sarcosine oxidase.

ABSTRACT: A precise 100-ns molecular dynamics simulation in aquo was performed for the heterotetrameric sarcosine oxidase bound with a substrate analogue, dimethylglycine. The spatial region including the protein was divided into small rectangular cells. The average number of the water molecules locating within each cell was calculated based on the simulation trajectory. The clusters of the cells filled with water molecules were used to determine the water channels. The narrowness of the channels, the average hydropathy indices of the residues of the channels, and the number of migration events of water molecules through the channels were consistent with the selective transport hypothesis whereby tunnel T3 is the pathway for the exit of the iminium intermediate of the enzyme reaction.

SUBMITTER: Watanabe G

PROVIDER: S-EPMC4736832 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Analysis of water channels by molecular dynamics simulation of heterotetrameric sarcosine oxidase.

Watanabe Go G Nakajima Daisuke D Hiroshima Akinori A Suzuki Haruo H Yoneda Shigetaka S

Biophysics and physicobiology 20151222

A precise 100-ns molecular dynamics simulation in aquo was performed for the heterotetrameric sarcosine oxidase bound with a substrate analogue, dimethylglycine. The spatial region including the protein was divided into small rectangular cells. The average number of the water molecules locating within each cell was calculated based on the simulation trajectory. The clusters of the cells filled with water molecules were used to determine the water channels. The narrowness of the channels, the ave ...[more]

PMID: 27493862

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Project description: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.

Project description:This Review explores the dynamic behavior of water within nanopores and biological channels in lipid bilayer membranes. We focus on molecular simulation studies, alongside selected structural and other experimental investigations. Structures of biological nanopores and channels are reviewed, emphasizing those high-resolution crystal structures, which reveal water molecules within the transmembrane pores, which can be used to aid the interpretation of simulation studies. Different levels of molecular simulations of water within nanopores are described, with a focus on molecular dynamics (MD). In particular, models of water for MD simulations are discussed in detail to provide an evaluation of their use in simulations of water in nanopores. Simulation studies of the behavior of water in idealized models of nanopores have revealed aspects of the organization and dynamics of nanoconfined water, including wetting/dewetting in narrow hydrophobic nanopores. A survey of simulation studies in a range of nonbiological nanopores is presented, including carbon nanotubes, synthetic nanopores, model peptide nanopores, track-etched nanopores in polymer membranes, and hydroxylated and functionalized nanoporous silica. These reveal a complex relationship between pore size/geometry, the nature of the pore lining, and rates of water transport. Wider nanopores with hydrophobic linings favor water flow whereas narrower hydrophobic pores may show dewetting. Simulation studies over the past decade of the behavior of water in a range of biological nanopores are described, including porins and β-barrel protein nanopores, aquaporins and related polar solute pores, and a number of different classes of ion channels. Water is shown to play a key role in proton transport in biological channels and in hydrophobic gating of ion channels. An overall picture emerges, whereby the behavior of water in a nanopore may be predicted as a function of its hydrophobicity and radius. This informs our understanding of the functions of diverse channel structures and will aid the design of novel nanopores. Thus, our current level of understanding allows for the design of a nanopore which promotes wetting over dewetting or vice versa. However, to design a novel nanopore, which enables fast, selective, and gated flow of water de novo would remain challenging, suggesting a need for further detailed simulations alongside experimental evaluation of more complex nanopore systems.

Dataset Information

Analysis of water channels by molecular dynamics simulation of heterotetrameric sarcosine oxidase.

Publications

Analysis of water channels by molecular dynamics simulation of heterotetrameric sarcosine oxidase.

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