Validating Solution Ensembles from Molecular Dynamics Simulation by Wide-Angle X-ray Scattering Data

Chen, Po-Chia; Hub, Jochen S.

doi:10.1016/j.bpj.2014.06.006

Cited by 138 publications

(225 citation statements)

References 65 publications

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“…1C). SAXS/WAXS patterns were computed following the explicit-solvent calculations we introduced recently (48,49). The protein was described by the CHARMM22 p force field (62).…”

Section: Methodsmentioning

confidence: 99%

“…To apply this strategy to TR-WAXS data, we recently developed an algorithm for the calculation of isotropic and anisotropic TR-SWAXS patterns from explicit-solvent MD simulations, which we here used to study the ultrafast dynamics after CO photodissociation in Mb. The calculations are fully based on explicit-solvent MD, thus accounting for scattering contributions from density modulations in the hydration layer (48,49).…”

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confidence: 99%

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Ultrafast anisotropic protein quake propagation after CO photodissociation in myoglobin

Brinkmann

Hub

2016

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

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"Protein quake" denotes the dissipation of excess energy across a protein, in response to a local perturbation such as the breaking of a chemical bond or the absorption of a photon. Femtosecond timeresolved small-and wide-angle X-ray scattering (TR-SWAXS) is capable of tracking such ultrafast protein dynamics. However, because the structural interpretation of the experiments is complicated, a molecular picture of protein quakes has remained elusive. In addition, new questions arose from recent TR-SWAXS data that were interpreted as underdamped oscillations of an entire protein, thus challenging the long-standing concept of overdamped global protein dynamics. Based on molecular-dynamics simulations, we present a detailed molecular movie of the protein quake after carbon monoxide (CO) photodissociation in myoglobin. The simulations suggest that the protein quake is characterized by a single pressure peak that propagates anisotropically within 500 fs across the protein and further into the solvent. By computing TR-SWAXS patterns from the simulations, we could interpret features in the reciprocalspace SWAXS signals as specific real-space dynamics, such as CO displacement and pressure wave propagation. Remarkably, we found that the small-angle data primarily detect modulations of the solvent density but not oscillations of the bare protein, thereby reconciling recent TR-SWAXS experiments with the notion of overdamped global protein dynamics.time-resolved SAXS/WAXS | free-electron laser | molecular dynamics F unctional protein dynamics occur on various timescales, ranging from tens of femtoseconds for bond breaking, up to milliseconds and seconds for large-scale conformational transitions or protein folding. Observing and explaining such transitions, if possible in a time-resolved manner, has remained a central goal of molecular biophysics. A popular model system used to study proteins dynamics has been the 18-kDa protein myoglobin (Mb), the protein of first known tertiary structure (1). Mb contains an iron-porphyrin heme group that reversibly binds small gas molecules such as molecular oxygen (O 2 ) or carbon monoxide (CO). Mb is abundant in the muscle tissue of vertebrates, where it plays an important role in the transport and storage of O 2 and in the biochemistry of nitric oxide (2, 3).Because the CO-iron bonds in a Mb ensemble can be coherently photolysed with a laser flash within only 50 fs (4), a range of time-resolved techniques has been applied to probe various aspects of the structural dynamics after CO photodissociation, such as energy dissipation, CO dynamics, or heme doming (5-15). Three-dimensional movies of Mb conformational transitions were derived by means of time-resolved crystallography, which recently reached subpicosecond time resolution (16-19). These experimental studies were complemented by several pioneering molecular-dynamics (MD) simulations that revealed the Mb dynamics with atomic detail, with some focus on heat dissipation, vibrational dynamics, as well as ligand migration (20-28).Time-re...

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“…1C). SAXS/WAXS patterns were computed following the explicit-solvent calculations we introduced recently (48,49). The protein was described by the CHARMM22 p force field (62).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Ultrafast anisotropic protein quake propagation after CO photodissociation in myoglobin

Brinkmann

Hub

2016

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

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“…13,[26][27][28][29][30][31] (A brief summary of 3D-RISM theory is given in Section V B.) X-ray scattering experiments on biomolecules compare the scattering intensity from the sample of interest to a "blank" with just solvent present, and report the difference, or "excess" intensity,…”

Section: A Calculation Of Saxs Profilesmentioning

confidence: 99%

Extracting water and ion distributions from solution x-ray scattering experiments

Nguyên

Pabit

Pollack

et al. 2016

The Journal of Chemical Physics

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Small-angle X-ray scattering measurements can provide valuable information about the solvent environment around biomolecules, but it can be difficult to extract solvent-specific information from observed intensity profiles. Intensities are proportional to the square of scattering amplitudes, which are complex quantities. Amplitudes in the forward direction are real, and the contribution from a solute of known structure (and from the waters it excludes) can be estimated from theory; hence, the amplitude arising from the solvent environment can be computed by difference. We have found that this "square root subtraction scheme" can be extended to non-zero q values, out to 0.1 Å −1 for the systems considered here, since the phases arising from the solute and from the water environment are nearly identical in this angle range. This allows us to extract aspects of the water and ion distributions (beyond their total numbers), by combining experimental data for the complete system with calculations for the solutes. We use this approach to test molecular dynamics and integral-equation (3D-RISM (three-dimensional reference interaction site model)) models for solvent structure around myoglobin, lysozyme, and a 25 base-pair duplex DNA. Comparisons can be made both in Fourier space and in terms of the distribution of interatomic distances in real space. Generally, computed solvent distributions arising from the MD simulations fit experimental data better than those from 3D-RISM, even though the total small-angle X-ray scattering patterns are very similar; this illustrates the potential power of this sort of analysis to guide the development of computational models. Published by AIP Publishing. [http://dx

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“…9,10,13,14,16 However, such calculations may face limitations in the wide-angle regime, where the internal structure of water and protein fluctuations become relevant. [31][32][33] In addition, conformational transitions may be subtle, suggesting that side chain and solvent fluctuations must be carefully averaged out before comparing structural models to experimental data. Another disadvantage of simple implicit solvent models is that they require fitting of free parameters associated with the solvation layer and the excluded solvent, thereby reducing the amount of available information.…”

Section: Introductionmentioning

confidence: 99%

Anisotropic time-resolved solution X-ray scattering patterns from explicit-solvent molecular dynamics

Brinkmann

Hub

2015

The Journal of Chemical Physics

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Time-resolved wide-angle X-ray scattering (TR-WAXS) is an emerging experimental technique used to track chemical reactions and conformational transitions of proteins in real time. Thanks to increased time resolution of the method, anisotropic TR-WAXS patterns were recently reported, which contain more structural information than isotropic patterns. So far, however, no method has been available to compute anisotropic WAXS patterns of biomolecules, thus limiting the structural interpretation. Here, we present a method to compute anisotropic TR-WAXS patterns from molecular dynamics simulations. The calculations accurately account for scattering of the hydration layer and for thermal fluctuations. For many photo-excitable proteins, given a low intensity of the excitation laser, the anisotropic pattern is described by two independent components: (i) an isotropic component, corresponding to common isotropic WAXS experiments and (ii) an anisotropic component depending on the orientation of the excitation dipole of the solute. We present a set of relations for the calculation of these two components from experimental scattering patterns. Notably, the isotropic component is not obtained by a uniform azimuthal average on the detector. The calculations are illustrated and validated by computing anisotropic WAXS patterns of a spheroidal protein model and of photoactive yellow protein. Effects due to saturated excitation at high intensities of the excitation laser are discussed, including opportunities to extract additional structural information by modulating the laser intensity.

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Validating Solution Ensembles from Molecular Dynamics Simulation by Wide-Angle X-ray Scattering Data

Cited by 138 publications

References 65 publications

Ultrafast anisotropic protein quake propagation after CO photodissociation in myoglobin

Ultrafast anisotropic protein quake propagation after CO photodissociation in myoglobin

Extracting water and ion distributions from solution x-ray scattering experiments

Anisotropic time-resolved solution X-ray scattering patterns from explicit-solvent molecular dynamics

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