General Framework for Studying the Dynamics of Folded and Nonfolded Proteins by NMR Relaxation Spectroscopy and MD Simulation

Prompers, Jeanine J.; Brüschweiler, Rafael

doi:10.1021/ja012750u

Cited by 193 publications

(294 citation statements)

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“…Such a procedure is a special case to the reporting of the dominant part of iRED eigenmodes together with their corresponding correlation times, from which the overall tumbling time can be modeled by fitting the correlation times of the five eigenmodes with the largest eigenvalues to the experimental data. 38 While in the present treatment isotropic overall tumbling is assumed, which is adequate for ubiquitin, 33 it can be easily extended to axially symmetric or fully anisotropic overall tumbling motion. 60 We find that for ubiquitin the modified AMBER99SB force field is better at reproducing both the amplitude and time scale of spin-relaxation active internal motions than AMBER99.…”

Section: Discussionmentioning

confidence: 99%

“…Such advances would be particularly beneficial for assessing simulations of (partially) unfolded and disordered protein systems whose overall motion is not separable from internal dynamics and for which an internal order parameter is not defined any longer. 38,61,62 …”

Section: Discussionmentioning

confidence: 99%

“…Because eq 7 contains only inner products, M ij is rotationally invariant; that is, it is valid in an arbitrary frame that makes no assumptions about separability between internal and overall tumbling motions. S 2 values can be computed from M by solving the eigenvalue problem M|m> ) λ m |m> (m ) 1, ..., N, where N ) number of interaction vectors e m ) and using 38 where the sum extends over the N-5 eigenvectors |m> corresponding to internal modes with eigenvalues λ m (i.e., all eigenvectors except those with the five largest eigenvalues). Equation 8 provides a computationally efficient way to determine order parameters without requiring the explicit removal of overall tumbling from the trajectory.…”

Section: Correlations Functions and Ordermentioning

confidence: 99%

“…Ubiquitin has also been successfully used as a model system for the MD investigation of NMR relaxation active motion in the past, yielding fundamental insight into the nature of internal protein dynamics. 34,37,38 More recently, a 0.2 µs ubiquitin MD trajectory calculated using the GROMOS96 43a1 force field 39 was reported by Nederveen and Bonvin (referred to as the "NB trajectory" from here on) from which both order parameters and spin relaxation parameters were computed. 28 The results of the current work indicate that the modified AMBER99SB force field performs qualitatively better than previous force fields at reproducing experimental order parameters, and it yields NMR spin relaxation parameters in near-quantitative agreement with experimental values.…”

Section: Introductionmentioning

confidence: 99%

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Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks: Application to the AMBER99SB Force Field

Showalter

Brüschweiler

2007

J. Chem. Theory Comput.

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Biological function of biomolecules is accompanied by a wide range of motional behavior. Accurate modeling of dynamics by molecular dynamics (MD) computer simulations is therefore a useful approach toward the understanding of biomolecular function. NMR spin relaxation measurements provide rigorous benchmarks for assessing important aspects of MD simulations, such as the amount and time scales of conformational space sampling, which are intimately related to the underlying molecular mechanics force field. Until recently, most simulations produced trajectories that exhibited too much dynamics particularly in flexible loop regions. Recent modifications made to the backbone and ψ torsion angle potentials of the AMBER and CHARMM force fields indicate that these changes produce more realistic molecular dynamics behavior. To assess the consequences of these changes, we performed a series of 5-20 ns molecular dynamics trajectories of human ubiquitin using the AMBER99 and AMBER99SB force fields for different conditions and water models and compare the results with NMR experimental backbone N-H S 2 order parameters. A quantitative analysis of the trajectories shows significantly improved agreement with experimental NMR data for the AMBER99SB force field as compared to AMBER99. Because NMR spin relaxation data (T 1 , T 2 , NOE) reflect the combined effects of spatial and temporal fluctuations of bond vectors, it is found that comparison of experimental and back-calculated NMR spin-relaxation data provides a more objective way of assessing the quality of the trajectory than order parameters alone. Analysis of a key mobile -hairpin in ubiquitin demonstrates that the dynamics of mobile sites are not only reduced by the modified force field, but the extent of motional correlations between amino acids is also markedly diminished.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Correlations Functions and Ordermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks: Application to the AMBER99SB Force Field

Showalter

Brüschweiler

2007

J. Chem. Theory Comput.

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252

277

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“…17 Prompers and Brüschweiler combined molecular dynamics with NMR relaxation spectroscopy to study the dynamics of folded and unfolded proteins. 18 Zagrovic et al found that the mean structure averaged over unfolded ensemble of three different folds small proteins are nativelike. 19 Experimental information, such as NMR residual dipolar couplings, can be used as constraints to select unfolded state structures.…”

Section: Introductionmentioning

confidence: 99%

Constrained proper sampling of conformations of transition state ensemble of protein folding

Lin

Jian

et al. 2011

The Journal of Chemical Physics

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Characterizing the conformations of protein in the transition state ensemble (TSE) is important for studying protein folding. A promising approach pioneered by Vendruscolo et al. [Nature (London) 409, 641 (2001) (2007)] to generate TSE conformations of acylphosphatase of 98 residues that satisfy the φ-value constraints, as well as the criterion that each conformation has a folding probability of 0.5 by Monte Carlo simulations. We adopt a two stage process and first generate 5000 contact maps satisfying the φ-value constraints. Each contact map is then used to generate 1000 properly weighted conformations. After clustering similar conformations, we obtain a set of properly weighted samples of 4185 candidate clusters. Representative conformation of each of these cluster is then selected and 50 runs of Markov chain Monte Carlo (MCMC) simulation are carried using a regrowth move set. We then select a subset of 1501 conformations that have equal probabilities to fold and to unfold as the set of TSE. These 1501 samples characterize well the distribution of transition state ensemble conformations of acylphosphatase. Compared with previous studies, our approach can access much wider conformational space and can objectively generate conformations that satisfy the φ-value constraints and the criterion of 0.5 folding probability without bias. In contrast to previous studies, our results show that transition state conformations are very diverse and are far from nativelike when measured in cartesian root-mean-square deviation (cRMSD): the average cRMSD between TSE conformations and the native structure is 9.4 Å for this short protein, instead of 6 Å reported in previous studies. In addition, we found that the average fraction of native contacts in the TSE is 0.37, with enrichment in native-like β-sheets and a shortage of long range contacts, suggesting such contacts form at a later stage of folding. We further calculate the first passage time of folding of TSE conformations through calculation of physical time associated with the regrowth moves in MCMC simulation through mapping such moves to a Markovian state model, whose transition time was obtained by Langevin dynamics simulations. Our results indicate that despite the large structural diversity of the TSE, they are characterized by similar folding time. Our approach is general and can be used to study TSE in other macromolecules.

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Order Parameters and Conformational Entropies Derived from Combined NMR and Molecular Dynamics Approach

Akke

2014

eMagRes

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General Framework for Studying the Dynamics of Folded and Nonfolded Proteins by NMR Relaxation Spectroscopy and MD Simulation

Cited by 193 publications

References 65 publications

Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks: Application to the AMBER99SB Force Field

Validation of Molecular Dynamics Simulations of Biomolecules Using NMR Spin Relaxation as Benchmarks: Application to the AMBER99SB Force Field

Constrained proper sampling of conformations of transition state ensemble of protein folding

Order Parameters and Conformational Entropies Derived from Combined NMR and Molecular Dynamics Approach

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