Computational studies of the interaction of myoglobin and xenon

Tilton, Robert D.; Singh, U. Chandra; Weiner, Scott J.; Connolly, Michael L.; Kuntz, Irwin D.; Kollman, Peter A.; Max, Nelson; Case, David A.

doi:10.1016/0022-2836(86)90374-8

Cited by 85 publications

(61 citation statements)

References 26 publications

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“…Like myoglobin, this is a heme-binding protein that requires oxygen to bind to the heme for its function. The large clusters of probes found in cytochrome P450cam may indicate multiple pathways along which oxygen can diffuse through the protein to and from the heme, in a similar way to the proposed diffusion of oxygen through cavities within myoglobin (Tilton et al, 1986).…”

Section: Interior Cavitiesmentioning

confidence: 73%

“…The total cavity volume of a protein of a given size shows no dependence on structural class. However, the cavity volume of proteins of similar size may differ substantially, possibly reflecting functional differences between the proteins (Rashin et al, 1986;Tilton et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…Although internal cavities have been referred to by the term "packing defect" (Connolly, 1985), there is evidence that the cavities in some proteins have a functional role, e.g., the diffusion of oxygen to the heme in myoglobin probably occurs through connected cavities within the protein molecule (Tilton et al, 1986). …”

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confidence: 99%

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Buried waters and internal cavities in monomeric proteins

1994

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We have analyzed the buried water molecules and internal cavities in a set of 75 high-resolution, nonhomologous, monomeric protein structures. The number of hydrogen bonds formed between each water molecule and the protein varies from 0 to 4, with 3 being most common. Nearly half of the water molecules are found in pairs or larger clusters. Approximately 90% are shown to be associated with large cavities within the protein, as determined by a novel program, PRO-ACT. The total volume of a protein's large cavities is proportional to its molecular weight and is not dependent on structural class. The largest cavities in proteins are generally elongated rather than globular. There are many more empty cavities than hydrated cavities. The likelihood of a cavity being occupied by a water molecule increases with cavity size and the number of available hydrogen bond partners, with each additional partner typically stabilizing the occupied state by 0.6 kcal/mol.

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Section: Interior Cavitiesmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Buried waters and internal cavities in monomeric proteins

1994

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“…Fluctuations in side-chain conformations are also thought to contribute to creating sites for Xe binding in proteins. 39 Although sites for Xe binding in proteins can be located by X-ray methods, NMR has the advantage of being able to characterize the binding dynamics in both the solid or solution phases. Polarization transfer from hyperpolarized 129 Xe to nuclei of residues near Xe binding sites in proteins will be particularly important in determining structure in proteins for which crystal structures are not available.…”

Section: Discussionmentioning

confidence: 99%

Exploring Surfaces and Cavities in Lipoxygenase and Other Proteins by Hyperpolarized Xenon-129 NMR

et al. 1999

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This paper presents an exploratory study of the binding interactions of xenon with the surface of several different proteins in the solution and solid states using both conventional and hyperpolarized 129 Xe NMR. The generation of hyperpolarized 129 Xe by spin exchange optical pumping affords an enhancement by 3-4 orders of magnitude of its NMR signal. As a result, it is possible to observe Xe directly bound to the surface of micromolar quantities of lyophilized protein.The highly sensitive nature of the 129 Xe line shape and chemical shift are used as indicators for the conditions most likely to yield maximal dipolar contact between 129 Xe nuclei and nuclear spins situated on the protein. This is an intermediate step toward achieving the ultimate goal of NMR enhancement of the binding-site nuclei by polarization transfer from hyperpolarized 129 Xe. The hyperpolarized 129 Xe spectra resulting from exposure of four different proteins in the lyophilized, powdered form have been examined for evidence of binding. Each of the proteins, namely, metmyoglobin, methemoglobin, hen egg white lysozyme, and soybean lipoxygenase, yielded a distinctly different NMR line shape. With the exception of lysozyme, the proteins all possess a paramagnetic iron center which can be expected to rapidly relax the 129 Xe and produce a net shift in its resonance position if the noble gas atom occupies specific binding sites near the iron. At temperatures from 223 to 183 K, NMR signals were observed in the 0-40 ppm chemical shift range, relative to Xe in the gas phase. The signals broadened and shifted downfield as the temperature was reduced, indicating that Xe is exchanging between the gas phase and internal or external binding sites of the proteins. Additionally, conventional 129 Xe NMR studies of metmyoglobin and lipoxygenase in the solution state are presented. The temperature dependence of the chemical shift and line shape indicate exchange of Xe between adsorption sites on lipoxygenase and Xe in the solvent on the slow to intermediate exchange time scale. The NMR results are compared with N 2 , Xe, and CH 4 gas adsorption isotherms. It is found that lipoxygenase is unique among the proteins studied in possessing a relatively high affinity for gas molecules, and in addition, demonstrating the most clearly resolved adsorbed 129 Xe NMR peak in the lyophilized state.

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“…These studies include the following simulations: (1) The diffusion of the ligands O2 (Case & Karplus, 1979;Case & McCammon, 1986; Kottalam & Case, 1988), Xe (Tilton et al, 1986), and CO (Elber & Karplus, 1990) from the heme-binding site in Mb and in leghemoglobin Nowak et al, 1991). (2) The simulation of the photodissociation of CO from Hb and from Mb (Sassaroli & Rousseau, 1986).…”

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confidence: 99%

Application of molecular dynamics and free energy perturbation methods to metalloporphyrin‐ligand systems ii: Co and dioxygen binding to myoglobin

Lopez

Kollman

1993

Protein Science

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The protein contribution to the relative binding affinity of the ligands CO and O2 toward myoglobin (Mb) has been simulated using free energy perturbation calculations. The tautomers of the His E7 residue are different for the oxymyoglobin (MbO2) and carboxymyoglobin (MbCO) systems. This was modeled by performing two‐step calculations that mutate the ligand and mutate the His E7 tautomers in separate steps. Differences in hydrogen bonding to the O2 and CO ligands were incorporated into the model. The O2 complex was calculated to be 2–3 kcal/mol more stable than the corresponding CO complex when compared to the same difference in an isolated heme control. This value agrees well with the experimental value of 2.0 kcal/mol. In qualitative agreement with experiments, the Fe‐C‐O bond is found to be bent (θ = 159.8°) with a small tilt (ϕ = 6.2°). The contributions made by each of the 29 residues — within the 9.0‐Å radius of the iron atom — to the free energy difference are separated into van der Waals and electrostatic contributions; the latter contributions are dominant. Aside from the proximal histidine and the heme group, the residues having the largest difference in free energy in mutating MbO2 → MbCO are His E7, Phe CD1, Phe CD4, Val E11, and Thr E10.

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Computational studies of the interaction of myoglobin and xenon

Cited by 85 publications

References 26 publications

Buried waters and internal cavities in monomeric proteins

Buried waters and internal cavities in monomeric proteins

Exploring Surfaces and Cavities in Lipoxygenase and Other Proteins by Hyperpolarized Xenon-129 NMR

Application of molecular dynamics and free energy perturbation methods to metalloporphyrin‐ligand systems ii: Co and dioxygen binding to myoglobin

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