NMR Order Parameter Determination from Long Molecular Dynamics Trajectories for Objective Comparison with Experiment

Abstract

Functional protein motions covering a wide range of time scales can be studied, among other techniques, by NMR and by molecular dynamics (MD) computer simulations. MD simulations of proteins now routinely extend into the hundreds of nanoseconds time scale range exceeding the overall tumbling correlation times of proteins in solution by several orders of magnitude. This provides a unique opportunity to rigorously validate these simulations by quantitative comparison with model-free order parameters derived from NMR relaxation experiments. However, presently there is no consensus on how such a comparison is best done. We address here how this can be accomplished in a way that is both efficient and objective. For this purpose, we analyze (15)N R1 and R2 and heteronuclear {(1)H}-(15)N NOE NMR relaxation parameters computed from 500 ns MD trajectories of 10 different protein systems using the model-free analysis. The resulting model-free S(2) order parameters are then used as targets for S(2) values computed directly from the trajectories by the iRED method by either averaging over blocks of variable lengths or by using exponentially weighted snapshots (wiRED). We find that the iRED results are capable of reproducing the target S(2) values with high accuracy provided that the averaging window is chosen 5 times the length of the overall tumbling correlation time. These results provide useful guidelines for the derivation of NMR order parameters from MD for a meaningful comparison with their experimental counterparts.

ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB

“…This calculation was performed using iRED, which does not require separability of local and global motions 48 . For this analysis, we averaged iRED results calculated for windows of length 5 times the tumbling correlation time (τ C ), as has been suggested to best reproduce the model-free S 2 order parameters 59 . This analysis was also repeated with window lengths found in previous publications, to facilitate comparison of results (see Supporting Information).…”

FF12MC: A revised AMBER forcefield and new protein simulation protocol

“…Although the S 2 simulations using FF12MCsm and FF14SB were performed for up to 100 ns smt , the best calculated S 2 parameters using FF12MCsm and FF14SB were not obtained on timescales that are close to five times the τ c s of the four proteins. This is partly because the stiffness of a protein exhibiting in the simulations using FF12MCsm or FF14SB differs from the stiffness using a forcefield—ff99SB_φψ(g24;CS)—that led to the five times τ c recommendation for best S 2 estimation …”

Residue-Specific Interactions of an Intrinsically Disordered Protein with Silica Nanoparticles and Their Quantitative Prediction

“…, Ref. [ 26 ] and references therein) directly proportional to the overall tumbling correlation time τ c of the nanoparticles, which can be estimated based on the Stokes-Einstein-Debye relationship $${\tau }_{\mathrm{c}}=\frac{V\eta }{k_{\mathrm{B}}T}$$where V is the hydrodynamic volume of a single SNP, η is the solvent (water) viscosity, k B is the Boltzmann constant, and T is the absolute temperature (see the Supporting Information for details). Therefore, $R_2^b{(}^{15}\mathrm{normalN}false)\approx 1.6\times {10}^3{\mathrm{s}}^{-1}$ is constant for all residues.…”