NO rebinding to myoglobin: a reactive molecular dynamics study

Meuwly, Markus; Becker, Oren M.; Stote, Roland H.; Karplus, Martin

doi:10.1016/s0301-4622(02)00093-5

Cited by 109 publications

(200 citation statements)

References 69 publications

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“…This approach was used in a variety of studies such as ligand entry, escape, dynamic control of tunnel opening, and various mutagenesis studies, yielding results that are in excellent agreement with the experimentally determined rates (42)(43)(44)(45)50). Because the reaction coordinate involves the formation of the O 2 -iron bond, a process not allowed in the standard MD force field, we introduced a Morse potential to describe this coordination (51),…”

Section: Methodsmentioning

confidence: 79%

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

Boechi

Arrar

Martí

et al. 2013

Journal of Biological Chemistry

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Background:The distal histidine in myoglobin is thought to act as a gate regulating oxygen uptake. Results:Neither the open nor closed conformation hinders oxygen uptake; a hydrophobic site is more apparent in the open conformation. Conclusion:The driving force for ligand uptake is the hydrophobic effect. Significance: This amplifies our understanding of the mechanisms through which proteins regulate ligand uptake.

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Section: Methodsmentioning

confidence: 79%

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

Boechi

Arrar

Martí

et al. 2013

Journal of Biological Chemistry

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“…Other parameters required to describe the heme-ligand interactions were taken from Kuczera et al (18) and Meuwly and coworkers (15). The computational setup follows a similar procedure to previous studies of the photodissociation of MbNO and MbCO (8,9,15). The native protein structure was taken from the x-ray structure of Kuriyan and coworkers (19), to which hydrogen atoms were added.…”

Section: Methods: Details Of the Molecular Dynamics (Md) Simulationsmentioning

confidence: 99%

“…The photodissociation event was modeled by the ''sudden'' approximation, as used previously (8,9,15). The Fe-C bond is deleted and the potential parameters for the bound state are replaced by those for the dissociated state.…”

Section: Methods: Details Of the Molecular Dynamics (Md) Simulationsmentioning

confidence: 99%

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CO migration in native and mutant myoglobin: Atomistic simulations for the understanding of protein function

Nutt

Meuwly

2004

Proc. Natl. Acad. Sci. U.S.A.

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Molecular dynamics simulations of the events after the photodissociation of CO in the myoglobin mutant L29F in which leucine is replaced by phenylalanine are reported. Using both classical and mixed quantum-classical molecular dynamics calculations, we observed the rapid motion of CO away from the distal heme pocket to other regions of the protein, in agreement with recent experimental results. The experimentally observed and calculated infrared spectra of CO after dissociation are also in good agreement. We compared the results with data from simulations of WT myoglobin. As the time resolution of experimental techniques is increased, theoretical methods and models can be validated at the atomic scale by direct comparison with experiment. R ecently, the time-resolved infrared spectrum and x-ray diffraction of photodissociated 13 CO in myoglobin (Mb) have been reported for a particular mutant, L29F (1). In this mutant the leucine (L) residue at position 29 is replaced by a phenylalanine (F) (see Fig. 1). This mutation introduces a bulky phenyl side chain into the distal heme pocket that can be expected to have an impact on the dynamics after photodissociation. It was previously found that the equilibrium constants for O 2 binding are larger by a factor of 15 in L29F compared to native Mb (2). This difference was interpreted as due to stabilizing interactions between the bound dioxygen and atoms of the phenyl ring. The infrared experiments, carried out at 283 K, found that the characteristic infrared absorption band for CO in the native Mb changes profoundly in the case of the L29F mutant (1). The well known bimodal distribution, indicative of the population of different binding sites [conformational substates B1 and B2, which differ in the orientation of the CO (3, 4), and possibly B3, which can only be populated by extended illumination in native MbCO (5)] is fundamentally altered. For L29F, the bimodal structure of the infrared spectrum disappears after Ϸ100 ps, whereas for native Mb it persists for 100 ns. This effect was explained by the escape of CO from the primary docking site within the distal heme pocket (Fig. 1) to neighboring sites within the protein on a time scale three orders of magnitude faster than in the case of native Mb (1).Previous theoretical investigations of the ligand dynamics of CO in myoglobin focused mostly on the short time scale and have considered effects after dissociation of the ligand from the iron on the picosecond time scale (6, 7). Some of the investigations used a three-site model for the CO ligand (8). This model correctly describes the static dipole and quadrupole moment of CO. Recently, we developed a refined model that uses fluctuating charges on the C and O atom sites and at the center of mass (9). This model reproduces high-level ab initio calculations of the dipole and quadrupole moment over a wide range of intermolecular separations (10, 11) and allows the calculation of the infrared spectrum associated with the CO vibration. The model correctly describes the experimen...

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“…8, 49 Meuwly, Karplus, and co-workers 11 chose a different reactive model to describe the ligand rebinding process. A structural criterion for the reaction was defined, and once the system meets the criterion for a transition, the transition is assumed to always occur.…”

Section: ■ Introductionmentioning

confidence: 99%

Dynamics of Methionine Ligand Rebinding in Cytochrome c

2012

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Geminate recombination of the methionine ligand to the heme iron in ferrous cytochrome c protein following photodissociation displays rich kinetics. It is of particular interest to develop an understanding of fast and slow rebinding time scales, observed in experimental studies, in terms of features of the underlying complex energy landscape. The classical empirical force field in the heme pocket has been extended by incorporating ab initio potential energy surface calculations representing the ground singlet state and quintet state associated with methionine bond breaking and rebinding. An algorithm based on the Landau−Zener nonadiabatic transition theory has been employed to model the electronic surface hopping between two spin states during the process of ligand dissociation and recombination. Multiple conformational substates of the dissociated methionine ligand are found to participate in the reaction dynamics. Varying time scales for interconversion between substates lead to a mechanism elucidating the fast and slow rebinding time scales. The reaction system may be understood in terms of a two-dimensional reaction coordinate distinctly separated from the coupled bath of surrounding protein and solvent degrees of freedom. Insights into the reaction dynamics provided by this study lead to suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of ligand−protein binding. ■ INTRODUCTIONGeminate recombination of axial ligands to the iron atom in heme proteins, as one of the key steps of protein global structural dynamics and allostery, has been of great interest and widely studied both experimentally and theoretically in the past decades. Many of those studies have been dedicated to diatomic axial ligands, such as CO, NO, and O 2 in globins.1−27 From those studies, a deep and general understanding of protein dynamics, in terms of transitions between conformational substates, has developed and formed the foundation for modern "energy landscape" theories of protein dynamics and thermodynamics. In spite of this success, a rigorous understanding of molecular reaction dynamics for ligand rebinding in myoglobin has proven elusive. The Agmon−Hopfield 8 and Champion-Srajer 28,29 models of ligand rebinding define specific reaction coordinates for the rebinding process but also include an undefined protein coordinate as an essential component of the multidimensional reaction coordinate in addition to the surrounding bath. Although heme−ligand dissociation in heme proteins usually does not occur under normal conditions, heme−ligand bond breaking and rebinding take place during the process of internal and external ligand switching or competition in neuroglobin 30,31 as well as in a specific group of heme-based sensor proteins such as Ec DOS, DOSH, and CooA. 7,32,33 Understanding the kinetics and thermodynamics of internal ligand binding is essential to our knowledge of the composition and function of these heme proteins.Cytochrome c (cyt c) (Figure 1) is an essential ...

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NO rebinding to myoglobin: a reactive molecular dynamics study

Cited by 109 publications

References 69 publications

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

Hydrophobic Effect Drives Oxygen Uptake in Myoglobin via Histidine E7

CO migration in native and mutant myoglobin: Atomistic simulations for the understanding of protein function

Dynamics of Methionine Ligand Rebinding in Cytochrome c

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