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Replica exchange improves sampling in low-resolution docking stage of RosettaDock.

Zhang Z, Lange OF - PLoS ONE (2013)

Bottom Line: A benchmark of 30 complexes starting from structures of the unbound binding partners shows improved performance for ReplicaDock and ZDOCK when compared to shotgun sampling at equal or less computational expense.ReplicaDock and ZDOCK consistently reach lower energies and generate significantly more near-native conformations than shotgun sampling.Additionally, the refined ReplicaDock ensembles reach significantly lower interface energies and many previously hidden features of the docking energy landscape become visible when ReplicaDock is applied.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular NMR and Munich Center for Integrated Protein Science, Department Chemie, Technische Universität München, Garching, Germany.

ABSTRACT
Many protein-protein docking protocols are based on a shotgun approach, in which thousands of independent random-start trajectories minimize the rigid-body degrees of freedom. Another strategy is enumerative sampling as used in ZDOCK. Here, we introduce an alternative strategy, ReplicaDock, using a small number of long trajectories of temperature replica exchange. We compare replica exchange sampling as low-resolution stage of RosettaDock with RosettaDock's original shotgun sampling as well as with ZDOCK. A benchmark of 30 complexes starting from structures of the unbound binding partners shows improved performance for ReplicaDock and ZDOCK when compared to shotgun sampling at equal or less computational expense. ReplicaDock and ZDOCK consistently reach lower energies and generate significantly more near-native conformations than shotgun sampling. Accordingly, they both improve typical metrics of prediction quality of complex structures after refinement. Additionally, the refined ReplicaDock ensembles reach significantly lower interface energies and many previously hidden features of the docking energy landscape become visible when ReplicaDock is applied.

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Interface RMSD vs. Interface Energy after refinement for all the 30 unbound docking targets.The red dots represent the RelaxedNative ensembles(Results). The interface RMSD is shown on the x-axis, the interface energy on the y-axis. The same energy range is used for displaying both, shotgun sampling (blue) and ReplicaDock (black), results of each target, respectively. The vertical gray lines correspond to I_rms of 5.0 Å, and the two horizontal gray lines correspond to interface energy −4 and −8 Rosetta Energy Units.
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pone-0072096-g005: Interface RMSD vs. Interface Energy after refinement for all the 30 unbound docking targets.The red dots represent the RelaxedNative ensembles(Results). The interface RMSD is shown on the x-axis, the interface energy on the y-axis. The same energy range is used for displaying both, shotgun sampling (blue) and ReplicaDock (black), results of each target, respectively. The vertical gray lines correspond to I_rms of 5.0 Å, and the two horizontal gray lines correspond to interface energy −4 and −8 Rosetta Energy Units.

Mentions: The main observations for ReplicaDock for targets 1ppf and 1mlc are a) that much lower energies are sampled, b) that distinct energy funnels are sampled densely, and c) that for 1ppf the native energy funnel is sampled densely. Next, we ask whether similar differences in behavior between shotgun and ReplicaDock are observable for all 30 targets. Indeed, equivalent scatter plots of all targets (Figure 5) show similar differences between shotgun and ReplicaDock as already observed for targets 1ppf and 1mlc. To quantify, we computed histograms of the lowest energies sampled per target by the respective approaches (shotgun, ZDOCK, ReplicaDock and RelaxedNative). Whether we focus on the lowest 0.1%, 1% or 5% of decoys, energies of shotgun ensembles are higher for all targets, and even the RelaxedNative ensembles often do not reach energies as low as ReplicaDock (Figure 6). Energies of refined ZDOCK conformations are in-between those of ReplicaDock and shotgun. These results demonstrate that the conformations in the centroid ReplicaDock ensemble are well poised to reach low interface energies in the subsequent all-atom refinement.


Replica exchange improves sampling in low-resolution docking stage of RosettaDock.

Zhang Z, Lange OF - PLoS ONE (2013)

Interface RMSD vs. Interface Energy after refinement for all the 30 unbound docking targets.The red dots represent the RelaxedNative ensembles(Results). The interface RMSD is shown on the x-axis, the interface energy on the y-axis. The same energy range is used for displaying both, shotgun sampling (blue) and ReplicaDock (black), results of each target, respectively. The vertical gray lines correspond to I_rms of 5.0 Å, and the two horizontal gray lines correspond to interface energy −4 and −8 Rosetta Energy Units.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756964&req=5

pone-0072096-g005: Interface RMSD vs. Interface Energy after refinement for all the 30 unbound docking targets.The red dots represent the RelaxedNative ensembles(Results). The interface RMSD is shown on the x-axis, the interface energy on the y-axis. The same energy range is used for displaying both, shotgun sampling (blue) and ReplicaDock (black), results of each target, respectively. The vertical gray lines correspond to I_rms of 5.0 Å, and the two horizontal gray lines correspond to interface energy −4 and −8 Rosetta Energy Units.
Mentions: The main observations for ReplicaDock for targets 1ppf and 1mlc are a) that much lower energies are sampled, b) that distinct energy funnels are sampled densely, and c) that for 1ppf the native energy funnel is sampled densely. Next, we ask whether similar differences in behavior between shotgun and ReplicaDock are observable for all 30 targets. Indeed, equivalent scatter plots of all targets (Figure 5) show similar differences between shotgun and ReplicaDock as already observed for targets 1ppf and 1mlc. To quantify, we computed histograms of the lowest energies sampled per target by the respective approaches (shotgun, ZDOCK, ReplicaDock and RelaxedNative). Whether we focus on the lowest 0.1%, 1% or 5% of decoys, energies of shotgun ensembles are higher for all targets, and even the RelaxedNative ensembles often do not reach energies as low as ReplicaDock (Figure 6). Energies of refined ZDOCK conformations are in-between those of ReplicaDock and shotgun. These results demonstrate that the conformations in the centroid ReplicaDock ensemble are well poised to reach low interface energies in the subsequent all-atom refinement.

Bottom Line: A benchmark of 30 complexes starting from structures of the unbound binding partners shows improved performance for ReplicaDock and ZDOCK when compared to shotgun sampling at equal or less computational expense.ReplicaDock and ZDOCK consistently reach lower energies and generate significantly more near-native conformations than shotgun sampling.Additionally, the refined ReplicaDock ensembles reach significantly lower interface energies and many previously hidden features of the docking energy landscape become visible when ReplicaDock is applied.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular NMR and Munich Center for Integrated Protein Science, Department Chemie, Technische Universität München, Garching, Germany.

ABSTRACT
Many protein-protein docking protocols are based on a shotgun approach, in which thousands of independent random-start trajectories minimize the rigid-body degrees of freedom. Another strategy is enumerative sampling as used in ZDOCK. Here, we introduce an alternative strategy, ReplicaDock, using a small number of long trajectories of temperature replica exchange. We compare replica exchange sampling as low-resolution stage of RosettaDock with RosettaDock's original shotgun sampling as well as with ZDOCK. A benchmark of 30 complexes starting from structures of the unbound binding partners shows improved performance for ReplicaDock and ZDOCK when compared to shotgun sampling at equal or less computational expense. ReplicaDock and ZDOCK consistently reach lower energies and generate significantly more near-native conformations than shotgun sampling. Accordingly, they both improve typical metrics of prediction quality of complex structures after refinement. Additionally, the refined ReplicaDock ensembles reach significantly lower interface energies and many previously hidden features of the docking energy landscape become visible when ReplicaDock is applied.

Show MeSH