[21] Analysis of diffuse scattering and relation to molecular motion

Clarage, James; Phillips, George N.

doi:10.1016/s0076-6879(97)77023-x

Cited by 33 publications

(31 citation statements)

References 24 publications

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“…Diffuse scattering intensity computed from a 600-ps dynamics trajectory on lysozyme does not reproduce the observed intensity from this system. Neither is there agreement between theory and experiment for a 150-ps trajectory of fully solvated myoglobin (12). Fig.…”

mentioning

confidence: 85%

A sampling problem in molecular dynamics simulations of macromolecules.

Clarage

Romo

Andrews

et al. 1995

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

196

170

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Correlations in low-frequency atomic displacements predicted by molecular dynamics simulations on the order of 1 ns are undersampled for the time scales currently accessible by the technique. This is shown with three different representations of the fluctuations in a macromolecule: the reciprocal space of crystallography using diffuse x-ray scattering data, real three-dimensional Cartesian space using covariance matrices of the atomic displacements, and the 3N-dimensional configuration space of the protein using dimensionally reduced projections to visualize the extent to which phase space is sampled. Experimental Tests of Molecular DynamicsClassical molecular dynamics is a computational technique to simulate the behaviors, both thermodynamic and dynamic, of an atomic model. In the long time limit, the sampled trajectory yields detailed information about the approximate model Hamiltonian. Shorter trajectories yield incomplete information and confound comparison of the model with experiment. Relatively short trajectories of biological macromolecules, on the order of 1 ns, have been used with reasonable success for a number of experimental comparisons-for example, crystallographic B values (1) from x-ray scattering, incoherent structure factors from neutron scattering (2, 3), and order parameters from NMR spectroscopy (4). Because these experimental techniques probe the movement of single atoms we can conclude that the amplitude and frequency of displacement for particular individual atoms in the protein are being simulated accurately.However, on the basis of such local results we cannot also conclude that these same molecular dynamics calculations accurately simulate, or converge on, the correlation between two or more atoms in a protein (e.g., whether one part of a protein tends to act concertedly with another). The state of our present models, then, is not completely tested by our experimental methods. In this article we consider a particular test set to measure the convergence of two-body properties in protein simulations.An experimental technique that is sensitive to statistics between pairs of atoms, and thus to collective behavior in macromolecules, is diffuse x-ray scattering (5, 6). All x-ray intensity on a detector besides the sharp Bragg peaks is typically ignored in structural studies. However, this remaining intensity, Diffuse scattering experiments on several proteins and nucleic acids (7-10) demonstrate that correlations in displacements of neighboring atoms fall off roughly exponentially with the distance between the atoms, with a characteristic length of 4-8 A. That is, (8iA8) = e(Wx(J)exp(-Jr| rjl/y), where the correlation length y is less than the dimension of the protein molecule. Thus, in analogy with liquid structures, where the correlations in atomicpositions decay approximately exponentially with pair separation, the motion in proteins is often called liquid-like, in the sense that correlations in atomic displacements fall off rapidly with distance.As a test of whether the pair corr...

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mentioning

confidence: 85%

A sampling problem in molecular dynamics simulations of macromolecules.

Clarage

Romo

Andrews

et al. 1995

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

196

170

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“…X-ray diffraction yields an ensemble-averaged picture of the protein structure: each photon simultaneously probes multiple unit cells that can vary because of internal rearrangements or changes to the crystal lattice. Bragg analysis of X-ray diffraction only yields the mean charge density of the unit cell, however, which fundamentally limits the information that can be obtained about protein dynamics (2,3).…”

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confidence: 99%

Measuring and modeling diffuse scattering in protein X-ray crystallography

Benschoten

Liu

González

et al. 2016

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

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X-ray diffraction has the potential to provide rich information about the structural dynamics of macromolecules. To realize this potential, both Bragg scattering, which is currently used to derive macromolecular structures, and diffuse scattering, which reports on correlations in charge density variations, must be measured. Until now, measurement of diffuse scattering from protein crystals has been scarce because of the extra effort of collecting diffuse data. Here, we present 3D measurements of diffuse intensity collected from crystals of the enzymes cyclophilin A and trypsin. The measurements were obtained from the same X-ray diffraction images as the Bragg data, using best practices for standard data collection. To model the underlying dynamics in a practical way that could be used during structure refinement, we tested translation-libration-screw (TLS), liquid-like motions (LLM), and coarse-grained normal-modes (NM) models of protein motions. The LLM model provides a global picture of motions and was refined against the diffuse data, whereas the TLS and NM models provide more detailed and distinct descriptions of atom displacements, and only used information from the Bragg data. Whereas different TLS groupings yielded similar Bragg intensities, they yielded different diffuse intensities, none of which agreed well with the data. In contrast, both the LLM and NM models agreed substantially with the diffuse data. These results demonstrate a realistic path to increase the number of diffuse datasets available to the wider biosciences community and indicate that dynamics-inspired NM structural models can simultaneously agree with both Bragg and diffuse scattering.protein dynamics | normal modes | structural biology | diffuse scattering | liquid-like motions X -ray crystallography can be a key tool for elucidating the structural basis of protein motions that play critical roles in enzymatic reactions, protein-protein interactions, and signaling cascades (1). X-ray diffraction yields an ensemble-averaged picture of the protein structure: each photon simultaneously probes multiple unit cells that can vary because of internal rearrangements or changes to the crystal lattice. Bragg analysis of X-ray diffraction only yields the mean charge density of the unit cell, however, which fundamentally limits the information that can be obtained about protein dynamics (2, 3).An inherent limitation in Bragg analysis is that models with different concerted motions can yield the same mean charge density (4). The traditional approach assumes a single structural model with individual atomic displacement parameters (B factors). Given enough data, anisotropic displacement parameters can be modeled. When the data are more limited, translation-libration-screw (TLS) refinement, which models rigid-body motions of subdomains (5), is often used [22% of Protein Data Bank (PDB) depositions (6, 7)]. Variations in the TLS domains can predict very different motions that agree equally well with the Bragg data (8, 9).Bragg analysis can be combined ...

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“…Modifications to the setup and data collection protocols include minimizing the amount of solvent around the crystal, choosing a low-background sample environment such as a helium tunnel, 80 and measuring and subtracting the background scattering that remains. 6 …”

Section: X-ray Scattering Theorymentioning

confidence: 99%

X-ray Scattering Studies of Protein Structural Dynamics

et al. 2017

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X-ray scattering is uniquely suited to the study of disordered systems and thus has the potential to provide insight into dynamic processes where diffraction methods fail. In particular, while X-ray crystallography has been a staple of structural biology for more than half a century and will continue to remain so, a major limitation of this technique has been the lack of dynamic information. Solution X-ray scattering has become an invaluable tool in structural and mechanistic studies of biological macromolecules where large conformational changes are involved. Such systems include allosteric enzymes that play key roles in directing metabolic fluxes of biochemical pathways, as well as large, assembly-line type enzymes that synthesize secondary metabolites with pharmaceutical applications. Furthermore, crystallography has the potential to provide information on protein dynamics via the diffuse scattering patterns that are overlaid with Bragg diffraction. Historically, these patterns have been very difficult to interpret, but recent advances in X-ray detection have led to a renewed interest in diffuse scattering analysis as a way to probe correlated motions. Here, we will review X-ray scattering theory and highlight recent advances in scattering-based investigations of protein solutions and crystals, with a particular focus on complex enzymes.

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[21] Analysis of diffuse scattering and relation to molecular motion

Cited by 33 publications

References 24 publications

A sampling problem in molecular dynamics simulations of macromolecules.

A sampling problem in molecular dynamics simulations of macromolecules.

Measuring and modeling diffuse scattering in protein X-ray crystallography

X-ray Scattering Studies of Protein Structural Dynamics

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