Physics-based protein structure refinement through multiple molecular dynamics trajectories and structure averaging

Abstract

We used molecular dynamics (MD) simulations for structure refinement of Critical Assessment of Techniques for Protein Structure Prediction 10 (CASP10) targets. Refinement was achieved by selecting structures from the MD-based ensembles followed by structural averaging. The overall performance of this method in CASP10 is described, and specific aspects are analyzed in detail to provide insight into key components. In particular, the use of different restraint types, sampling from multiple short simulations versus a single long simulation, the success of a quality assessment criterion, the application of scoring versus averaging, and the impact of a final refinement step are discussed in detail.

Keywords: CASP; protein; quality assessment; scoring; structure prediction.

Figure 1

Flowchart of the refinement protocol, from simulation to model selection

Figure 2

Subset selection based on normalized iRMSD and DFIRE scores from the replicas in set 1 with corr(iRMSD,DFIRE)<0.4 for TR674. The structures shown in the lower left corner of the scatter plot as green triangles were selected for averaging.

Figure 3

Initial model (blue), refined (green) and native (magenta) for (a) TR662, (b) TR723, (c) TR738 and (d) TR674

Figure 4

Sampling efficiency toward native, showing the cumulative minimum ΔRMSD (top) and cumulative maximum ΔGDT-HA (bottom), comparing the single 200 ns MD simulations (red) vs. 10×20 ns MD simulations (green) averaged over 27 CASP10 targets.