Crankshaft motions of the polypeptide backbone in molecular dynamics simulations of human type-α transforming growth factor

Fadel, Addi R.; Jin, Dan; Montelione, Gaetano T.; Levy, Ronald M.

doi:10.1007/bf00211787

Cited by 72 publications

(97 citation statements)

References 26 publications

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“…Within the secondary structure elements of DHFR (Fig. S3), we observed that the crankshaft motion dominates the fluctuations of the peptide planes (27,51), in which the C α atoms essentially remain fixed and the largest displacements are observed for the carbonyl oxygens and amide protons. We also observed signs of coupling between the motions of peptide planes joined by hydrogen bonds within regular elements of secondary structure (35,50,52).…”

Section: Discussionmentioning

confidence: 84%

“…qFit and related ensemble methods have an advantage over anisotropic B-factor description because they are not limited to unimodal distributions (48,49). The qFit model of the DHFR E:FOL:NADP+ complex contains information on the anisotropy and coupling of motions that has been observed from molecular dynamics and NMR measurements (25,35,(50)(51)(52). Within the secondary structure elements of DHFR (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Integrated description of protein dynamics from room-temperature X-ray crystallography and NMR

Fenwick

Bedem

Fraser

et al. 2014

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

158

155

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Detailed descriptions of atomic coordinates and motions are required for an understanding of protein dynamics and their relation to molecular recognition, catalytic function, and allostery. Historically, NMR relaxation measurements have played a dominant role in the determination of the amplitudes and timescales (picosecond-nanosecond) of bond vector fluctuations, whereas high-resolution X-ray diffraction experiments can reveal the presence of and provide atomic coordinates for multiple, weakly populated substates in the protein conformational ensemble. Here we report a hybrid NMR and X-ray crystallography analysis that provides a more complete dynamic picture and a more quantitative description of the timescale and amplitude of fluctuations in atomic coordinates than is obtainable from the individual methods alone. Order parameters (S 2 ) were calculated from single-conformer and multiconformer models fitted to room temperature and cryogenic X-ray diffraction data for dihydrofolate reductase. Backbone and side-chain order parameters derived from NMR relaxation experiments are in excellent agreement with those calculated from the room-temperature single-conformer and multiconformer models, showing that the picosecond timescale motions observed in solution occur also in the crystalline state. These motions are quenched in the crystal at cryogenic temperatures. The combination of NMR and X-ray crystallography in iterative refinement promises to provide an atomic resolution description of the alternate conformational substates that are sampled through picosecond to nanosecond timescale fluctuations of the protein structure. The method also provides insights into the structural heterogeneity of nonmethyl side chains, aromatic residues, and ligands, which are less commonly analyzed by NMR relaxation measurements.B factor | nuclear magnetic resonance | atomic displacement parameters | Lipari-Szabo T he conformational dynamics of proteins play an important role in their functional mechanisms, influencing such diverse processes as conformational selection in molecular recognition (1), catalytic function (2, 3), and allosteric regulation (4). To understand the atomic motions that underlie protein dynamics and configurational entropy, it has become increasingly important to study both the timescales of motions and how those motions are manifest in the structure as coordinate changes. Two complementary methods are high-resolution X-ray crystallography and NMR spectroscopy, which provide coordinate precision and probe motions within well-defined timescales, respectively. The combination of X-ray and NMR data has thus far been limited to coordinate refinement because no rigorous framework exists to connect the coordinates and motional timescales (5-7).Proteins are not rigid and constantly sample distinct conformational substates (8). The coordinates derived from X-ray diffraction are accompanied by atomic displacement parameters or B factors that are related to the displacements of the atoms from their mean positions (9). B ...

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Integrated description of protein dynamics from room-temperature X-ray crystallography and NMR

Fenwick

Bedem

Fraser

et al. 2014

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

158

155

View full text Add to dashboard Cite

show abstract

“…In Fig. 1b, we provide a summary of the correlation analysis, where the crankshaft motion, a rotation of the peptide plane about the C a i À 1 -C a i axis that leads to the anti-correlation of c i À 1 and f i often observed in MD simulations, is shown in italics 24 . The crankshaft motion is equivalent to that put forward in the onedimensional Gaussian axial fluctuation model (1D-GAF) of the protein backbone and to the g motion of the related 3D-GAF motional model, the amplitudes of which have been extensively studied by NMR spectroscopy 20,21,[25][26][27] .…”

Section: Resultsmentioning

confidence: 99%

Correlated motions are a fundamental property of β-sheets

et al. 2014

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Correlated motions in proteins can mediate fundamental biochemical processes such as signal transduction and allostery. The mechanisms that underlie these processes remain largely unknown due mainly to limitations in their direct detection. Here, based on a detailed analysis of protein structures deposited in the protein data bank, as well as on state-of-the art molecular simulations, we provide general evidence for the transfer of structural information by correlated backbone motions, mediated by hydrogen bonds, across b-sheets. We also show that the observed local and long-range correlated motions are mediated by the collective motions of b-sheets and investigate their role in large-scale conformational changes. Correlated motions represent a fundamental property of b-sheets that contributes to protein function.

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“…[7,[13][14][15] We have also calculated 2D CCR maps for the C'/C'ÀC a CCR rate, which demonstrate the strong dependence of this rate on the orientation of the C'-shift tensor and variations in s ab (Supporting Information).…”

Section: Methodsmentioning

confidence: 99%

“…[7,9,[13][14][15] Whereas CCR processes in principle contain an enormous amount of information, the interpretation of these relaxation rates must be treated with great care. For example, a CSA/DD relaxation process depends on many factors, including the local molecular structure, the magnitude of the CSA and orientation of the shift tensor in the fixed molecular frame, and local anisotropic dynamics.…”

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confidence: 99%

Local Structure and Anisotropic Backbone Dynamics from Cross‐Correlated NMR Relaxation in Proteins

2005

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The molecular function of biomacromolecules is determined by both their 3D structure and conformational dynamics. NMR cross-correlated relaxation (CCR) contains information about local structure and local anisotropic dynamics. CCR arises from the interference of two relaxation mechanisms such as chemical shift anisotropy (CSA) and dipoledipole (DD) interactions, which are described by tensors in 3D space, and contains information about the relative orientation of these tensors and their correlated motion. [1][2][3][4] In this respect, CCR rates involving CSA tensors are most useful, as they sample local structure and dynamics along three orthogonal axes. Over the past few years, numerous NMR experiments have been designed to measure crosscorrelated relaxation rates to determine local molecular geometry, [3,5] to study local dynamics, [6][7][8][9] and to characterize chemical-shift tensors in solution.[10-12] Different models of anisotropic local motion of the peptide plane have been discussed. [7,9,[13][14][15] Whereas CCR processes in principle contain an enormous amount of information, the interpretation of these relaxation rates must be treated with great care. For example, a CSA/DD relaxation process depends on many factors, including the local molecular structure, the magnitude of the CSA and orientation of the shift tensor in the fixed molecular frame, and local anisotropic dynamics.[2] To simplify this problem, the magnitude of the CSA and orientation of the shift tensor, both of which are difficult to access experimentally and theoretically, are often treated as fixed invariable parameters. Alternatively, the effect of dynamics is included through a generalized (isotropic) order parameter, which represents a considerable simplification to the complex hierarchy of internal anisotropic dynamic modes that characterize the local motion of the peptide plane. Recently, the vector fluctuations of N À H and C'ÀC a bonds were monitored by studying the temperature dependence of cross-correlated relaxation rates rather than their absolute values, thereby diminishing the influence of uncertainties in CSA parameters.

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Crankshaft motions of the polypeptide backbone in molecular dynamics simulations of human type-α transforming growth factor

Cited by 72 publications

References 26 publications

Integrated description of protein dynamics from room-temperature X-ray crystallography and NMR

Integrated description of protein dynamics from room-temperature X-ray crystallography and NMR

Correlated motions are a fundamental property of β-sheets

Local Structure and Anisotropic Backbone Dynamics from Cross‐Correlated NMR Relaxation in Proteins

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