Importance of the CMAP Correction to the CHARMM22 Protein Force Field: Dynamics of Hen Lysozyme

Buck, Matthias; Bouguet‐Bonnet, Sabine; Pastor, Richard W.; MacKerell, Alexander D.

doi:10.1529/biophysj.105.078154

Cited by 342 publications

(361 citation statements)

References 11 publications

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“…On average, the GROMOS96 force field reproduces the order parameters of the rigid sites in ubiquitin quite well, 28 and the CHARMM C22/CMAP force field performs similarly well for the rigid sites of hen lysozyme. 23 By contrast, mobile regions of ubiquitin, such as the -hairpin loop and several of the loops closer to the Cterminus of the protein, turn out to be too floppy in the AMBER99 simulation, whereas they tend to be in good agreement with experimental results in the AMBER99SB simulation (Figure 2). Plots of the AMBER99 order parameters computed after 1 and 20 ns correlated against the experimental data ( Figure 3A and C) suggest that the 1 ns order parameters are the best result for the AMBER99 trajectory.…”

Section: Comparison Of Calculated Order Parameters With Experimentmentioning

confidence: 81%

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.

254

277

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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: Comparison Of Calculated Order Parameters With Experimentmentioning

confidence: 81%

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.

254

277

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“…8,14,25 For example, Buck et al used a variant of method 1 in which they calculated S 2 as the value of the internal correlation function at 6 ns, a time comparable to the rotational correlation time of the protein lysozyme. 8 Markwick et al carried out several short MD simulations, each of a length comparable to the time scale of rotational motion, for the B3 domain of protein G. 25 In that work, S 2 values were calculated by applying method 2 to each individual simulation and then averaging the resulting values over all simulations. These modifications of methods 1 and 2 yielded S 2 values in good agreement with experimental values, although it is unclear whether these modifications could be used more generally to remove the effects of long-time scale dynamics on S 2 values calculated from MD simulations.…”

Section: Resultsmentioning

confidence: 99%

“…Backbone amide order parameters have been measured for more than 200 proteins and used to quantify changes in conformational flexibility associated with protein folding, molecular recognition, and catalysis. 4 Values of S 2 obtained from protein molecular dynamics (MD) simulations have been compared to those obtained from experiments to validate 6,7 and improve 8,9 MD simulations, and to aid in the interpretation of experiments. 10,11 Ubiquitin is a 76-residue protein that has been used as a model system for experimental and computational studies of protein structure and dynamics.…”

Section: Introductionmentioning

confidence: 99%

Microsecond Molecular Dynamics Simulation Shows Effect of Slow Loop Dynamics on Backbone Amide Order Parameters of Proteins

et al. 2008

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A molecular-level understanding of the function of a protein requires knowledge of both its structural and dynamic properties. NMR spectroscopy allows the measurement of generalized order parameters that provide an atomistic description of picosecond and nanosecond fluctuations in protein structure. Molecular dynamics (MD) simulation provides a complementary approach to the study of protein dynamics on similar time scales. Comparisons between NMR spectroscopy and MD simulations can be used to interpret experimental results and to improve the quality of simulation-related force fields and integration methods. However, apparent systematic discrepancies between order parameters extracted from simulations and experiments are common, particularly for elements of noncanonical secondary structure. In this paper, results from a 1.2 µs explicit solvent MD simulation of the protein ubiquitin are compared with previously determined backbone order parameters derived from NMR relaxation experiments [Tjandra, N.; Feller, S. E.; Pastor, R. W.; Bax, A. J. Am. Chem. Soc. 1995, 117, 12562-12566]. The simulation reveals fluctuations in three loop regions that occur on time scales comparable to or longer than that of the overall rotational diffusion of ubiquitin and whose effects would not be apparent in experimentally derived order parameters. A coupled analysis of internal and overall motion yields simulated order parameters substantially closer to the experimentally determined values than is the case for a conventional analysis of internal motion alone. Improved agreement between simulation and experiment also is encouraging from the viewpoint of assessing the accuracy of long MD simulations.

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“…Comparison with NMR parameters for lysozyme and ubiquitin-Hen egg white lysozyme has become a standard for evaluating the quality of force fields by comparing internal dynamics parameters calculated from MD simulations to NMR relaxation experiments [59][60][61][62][63] . The degree of backbone flexibility is specified by experimentally derived order parameters S 2 , which correspond to amide bond N-H librational motion.…”

Section: Force Field Validationmentioning

confidence: 99%

Comparison of multiple Amber force fields and development of improved protein backbone parameters

et al. 2006

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The ff94 force field that is commonly associated with the AMBER simulation package is one of the most widely used parameter sets for biomolecular simulation. After a decade of extensive use and testing, limitations in this force field, such as over stabilization of α-helices, were reported by us and other researchers. This led to a number of attempts to improve these parameters, resulting in a variety of "AMBER" force fields and significant difficulty in determining which should be used for a particular application. We show that several of these continue to suffer from inadequate balance between different secondary structure elements. In addition, the approach used in most of these studies neglected to account for the existence in AMBER of two sets of backbone φ/ψ dihedral terms. This led to parameter sets that provide unreasonable conformational preferences for glycine. We report here an effort to improve the φ/ψ dihedral terms in the ff99 energy function. Dihedral term parameters are based on fitting the energies of multiple conformations of glycine and alanine tetrapeptides from high level ab-initio quantum mechanical calculations. The new parameters for backbone dihedrals replace those in the existing ff99 force field. This parameter set, which we denote ff99SB, achieves a better balance of secondary structure elements as judged by improved distribution of backbone dihedrals for glycine and alanine with respect to PDB survey data. It also accomplishes improved agreement with published experimental data for conformational preferences of short alanine peptides, and better accord with experimental NMR relaxation data of test protein systems.

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Importance of the CMAP Correction to the CHARMM22 Protein Force Field: Dynamics of Hen Lysozyme

Cited by 342 publications

References 11 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

Microsecond Molecular Dynamics Simulation Shows Effect of Slow Loop Dynamics on Backbone Amide Order Parameters of Proteins

Comparison of multiple Amber force fields and development of improved protein backbone parameters

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