Limits...
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.

Show MeSH
Interface RMSD vs. Interface Energy after refinement on target 1ppf and 1mlc.A) and C) refinement of shotgun sampling generated ensembles, B) and D) refinement of ReplicaDock generated ensembles. The red dots represent the RelaxedNative ensembles (Results).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3756964&req=5

pone-0072096-g004: Interface RMSD vs. Interface Energy after refinement on target 1ppf and 1mlc.A) and C) refinement of shotgun sampling generated ensembles, B) and D) refinement of ReplicaDock generated ensembles. The red dots represent the RelaxedNative ensembles (Results).

Mentions: We first introduce the typical differences between refined shotgun and ReplicaDock ensembles at the example of target 1ppf and 1mlc. As shown in Figure 4A, the refined shotgun ensemble of target 1ppf (blue) is higher in energy than the RelaxedNative ensemble (red). Only 3–4 isolated conformations reach significantly lower energies. The ReplicaDock ensemble, on the contrary, shows three distinct energy funnels that are well sampled (Figure 4B). One of the funnels coincides in form and position with the funnel formed by the RelaxedNative structures, demonstrating that the native energy basin has been found and is well sampled. But unfortunately it is neither the lowest nor the most pronounced energy funnel, rendering discrimination of native from non-native decoys challenging. Apparently, the Rosetta all-atom energy function features at least three well-resolved energy funnels for this target complex, which is confirmed by finding corresponding clusters that are well populated (data not shown). All three of these funnels remain poorly sampled with shotgun sampling. For target 1mlc the RelaxedNative conformations have higher energies than the shotgun or ReplicaDock ensembles (Figure 4C+D). This points to deficiencies of the energy function. However, also for 1mlc shotgun sampling produces only sporadic sampling of low energies, whereas ReplicaDock detects distinct funnels in the energy landscape.


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 on target 1ppf and 1mlc.A) and C) refinement of shotgun sampling generated ensembles, B) and D) refinement of ReplicaDock generated ensembles. The red dots represent the RelaxedNative ensembles (Results).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0072096-g004: Interface RMSD vs. Interface Energy after refinement on target 1ppf and 1mlc.A) and C) refinement of shotgun sampling generated ensembles, B) and D) refinement of ReplicaDock generated ensembles. The red dots represent the RelaxedNative ensembles (Results).
Mentions: We first introduce the typical differences between refined shotgun and ReplicaDock ensembles at the example of target 1ppf and 1mlc. As shown in Figure 4A, the refined shotgun ensemble of target 1ppf (blue) is higher in energy than the RelaxedNative ensemble (red). Only 3–4 isolated conformations reach significantly lower energies. The ReplicaDock ensemble, on the contrary, shows three distinct energy funnels that are well sampled (Figure 4B). One of the funnels coincides in form and position with the funnel formed by the RelaxedNative structures, demonstrating that the native energy basin has been found and is well sampled. But unfortunately it is neither the lowest nor the most pronounced energy funnel, rendering discrimination of native from non-native decoys challenging. Apparently, the Rosetta all-atom energy function features at least three well-resolved energy funnels for this target complex, which is confirmed by finding corresponding clusters that are well populated (data not shown). All three of these funnels remain poorly sampled with shotgun sampling. For target 1mlc the RelaxedNative conformations have higher energies than the shotgun or ReplicaDock ensembles (Figure 4C+D). This points to deficiencies of the energy function. However, also for 1mlc shotgun sampling produces only sporadic sampling of low energies, whereas ReplicaDock detects distinct funnels in the energy landscape.

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