Oxygen diffusion in minihemoglobin from Cerebratulus lacteus: a locally enhanced sampling study

Orlowski, Slawomir; Nowak, Wiesław

doi:10.1007/s00214-006-0139-8

Cited by 13 publications

(6 citation statements)

References 19 publications

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“…Tracing small ligands that travel inside a protein matrix provides data on transient cavities (57,(79)(80)(81). The LES technique, despite some of its drawbacks (68-72), is particularly practical for this type of study, since energy barriers are lowered due to an approximate character of the Hamiltonian of the system under study.…”

Section: No Dynamicsmentioning

confidence: 99%

Molecular Dynamics Simulations of the Photoactive Protein Nitrile Hydratase

Kubiak

Nowak

2008

Biophysical Journal

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Nitrile hydratase (NHase) is an enzyme used in the industrial biotechnological production of acrylamide. The active site, which contains nonheme iron or noncorrin cobalt, is buried in the protein core at the interface of two domains, alpha and beta. Hydrogen bonds between betaArg-56 and alphaCys-114 sulfenic acid (alphaCEA114) are important to maintain the enzymatic activity. The enzyme may be inactivated by endogenous nitric oxide (NO) and activated by absorption of photons of wavelength lambda < 630 nm. To explain the photosensitivity and to propose structural determinants of catalytic activity, differences in the dynamics of light-active and dark-inactive forms of NHase were investigated using molecular dynamics (MD) modeling. To this end, a new set of force field parameters for nonstandard NHase active sites have been developed. The dynamics of the photodissociated NO ligand in the enzyme channel was analyzed using the locally enhanced sampling method, as implemented in the MOIL MD package. A series of 1 ns trajectories of NHases shows that the protonation state of the active site affects the dynamics of the catalytic water and NO ligand close to the metal center. MD simulations support the catalytic mechanism in which a water molecule bound to the metal ion directly attacks the nitrile carbon.

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Section: No Dynamicsmentioning

confidence: 99%

Molecular Dynamics Simulations of the Photoactive Protein Nitrile Hydratase

Kubiak

Nowak

2008

Biophysical Journal

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“…The process of ligand dissociation is difficult to assess experimentally due to the complexity of protein structures, and in the absence of time-resolved crystallography experiments on ligand intermediates, the actual ligand expulsion pathways remain undetermined. , Therefore, uncovering the distributions of transport routes has been studied by many enhanced molecular dynamics (MD) methods, i.e. locally enhanced sampling, − targeted MD, steered MD, temperature accelerated MD, , hyperdynamics, , random acceleration MD (RAMD), supervised MD, metadynamics, , and, recently, the memetic algorithms . In the memetic algorithms, the process of the ligand expulsion from the protein is reconstructed on-the-fly by the efficient conformational space sampling of the protein interior using immune computation techniques in such a way that the obtained trajectory minimizes the functional of the interaction free-energy between the ligand and protein …”

Section: Introductionmentioning

confidence: 99%

Machine Learning Based Dimensionality Reduction Facilitates Ligand Diffusion Paths Assessment: A Case of Cytochrome P450cam

Rydzewski

Nowak

2016

J. Chem. Theory Comput.

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In this work we propose an application of a nonlinear dimensionality reduction method to represent the high-dimensional configuration space of the ligand-protein dissociation process in a manner facilitating interpretation. Rugged ligand expulsion paths are mapped into 2-dimensional space. The mapping retains the main structural changes occurring during the dissociation. The topological similarity of the reduced paths may be easily studied using the Fréchet distances, and we show that this measure facilitates machine learning classification of the diffusion pathways. Further, low-dimensional configuration space allows for identification of residues active in transport during the ligand diffusion from a protein. The utility of this approach is illustrated by examination of the configuration space of cytochrome P450cam involved in expulsing camphor by means of enhanced all-atom molecular dynamics simulations. The expulsion trajectories are sampled and constructed on-the-fly during molecular dynamics simulations using the recently developed memetic algorithms [ Rydzewski, J.; Nowak, W. J. Chem. Phys. 2015 , 143 ( 12 ), 124101 ]. We show that the memetic algorithms are effective for enforcing the ligand diffusion and cavity exploration in the P450cam-camphor complex. Furthermore, we demonstrate that machine learning techniques are helpful in inspecting ligand diffusion landscapes and provide useful tools to examine structural changes accompanying rare events.

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“…LES is a useful technique to speed up the diffusion rate of gases and improve the simulation statistics, which has been successfully used to investigate the transport of O 2 in hemoglobin, human cytoglobin, human ferritin, [Fe−Fe]-hydrogenase, quercetin 2,3-dioxygenase, and photoactive protein nitrile hydratase . As a mean field-based theory, LES is also used to increase the range of conformational sampling and has been applied to study protein-assisted RNA folding. , Within this method, N (15 in this study) noninteracting copies of O 2 molecule were built.…”

Section: Methodsmentioning

confidence: 99%

“…The existence of gas channels that connect the active site to the solvent in proteins has been proposed on the basis of experimental and computational investigations of various enzymes, such as O 2 migration pathways for myoglobin, − hemoglobin, − copper amine oxidase, [Fe]-hydrogenase, human ferritin protein, monooxygenase and oxidase flavoenzymes, and H 2 pathways for [Fe]-hydrogenase, [Ni−Fe]-hydrogenase, , and [Fe−Fe]-hydrogenase . In contrast, gas pathways in non-heme iron enzymes have only been characterized by molecular dynamics (MD) simulations for a small number of proteins so far, including O 2 channels in quercetin 2,3-dioxygenase and 12/15-lipoxygenase and NO diffusion in nitrile hydratase .…”

Section: Introductionmentioning

confidence: 99%

Locally Enhanced Sampling Study of Dioxygen Diffusion Pathways in Homoprotocatechuate 2,3-Dioxygenase

Liu

Zhao

et al. 2009

J. Phys. Chem. B

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Extradiol dioxygenases are characterized by activating dioxygen and incorporating both oxygen atoms into their substrates. Both experimental and theoretical investigations have been focused on the detection of intermediates in the reaction cycle in order to develop a general chemical mechanism of O(2) activation and insertion. However, little is known about the mechanism of how O(2) reaches the reaction sites of the related enzymes, which raises the question whether the rate of catalysis is limited by O(2) access to the active site. In this paper, two locally enhanced sampling molecular dynamics simulations were performed to determine the potential O(2) pathways inside a recently solved X-ray structure of homoprotocatechuate 2,3-dioxygenase. It is found that nominally identical subunits of the single homotetrameric structure contain distinct O(2) affinity diffusion pathways, which partly correlates with the observation of the simultaneous presence of three different reaction intermediates in four independent active sites. Residues that are critical for O(2) diffusion are also examined and discussed. In particular, we find that the breathing motion of the internal cavity defined by these residues results in O(2) migration process.

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Oxygen diffusion in minihemoglobin from Cerebratulus lacteus: a locally enhanced sampling study

Cited by 13 publications

References 19 publications

Molecular Dynamics Simulations of the Photoactive Protein Nitrile Hydratase

Molecular Dynamics Simulations of the Photoactive Protein Nitrile Hydratase

Machine Learning Based Dimensionality Reduction Facilitates Ligand Diffusion Paths Assessment: A Case of Cytochrome P450cam

Locally Enhanced Sampling Study of Dioxygen Diffusion Pathways in Homoprotocatechuate 2,3-Dioxygenase

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