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

Abstract

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.

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

“…Finally, our results reiterate 15,30 the need for caution in assessing simulation quality from comparisons with experimental values of S 2 . Furthermore, the improved agreement between experiment and simulation obtained in the present work by joint fitting of internal and overall motions to the simulation trajectory justifies detailed interpretation of long MD simulations of protein function.…”

Conformational dynamics of a crystalline protein from microsecond-scale molecular dynamics simulations and diffuse X-ray scattering

“…Indeed, use of NMR data for force field improvement provides an example of the potential impact of diffuse scattering. Early comparisons of MD to NMR data for staphylococcal nuclease revealed differences in the residue-by-residue backbone flexibility (58), and more recent force fields now do a much better job of reproducing the NMR data (59)(60)(61)(62). Another possibility is to use diffuse scattering for validating results obtained using schemes for increasing sampling (54)(55)(56)(57).…”

Simulations of the confinement of ubiquitin in self-assembled reverse micelles

“…40 We assume that the principal axis of the dipole-dipole tensor is parallel to the N-H bond. 54 The order parameters for residues Leu 8 ∼Thr 12, Glu 18 ∼Thr 22, Gly 47∼ Gln 49 decrease as we increase the sampling time. Those regions are mainly loop regions which connect beta-sheets and helix.…”