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Dimeric interactions and complex formation using direct coevolutionary couplings.

dos Santos RN, Morcos F, Jana B, Andricopulo AD, Onuchic JN - Sci Rep (2015)

Bottom Line: Therefore a systematic way to extract dimerization signals has been elusive.For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively.This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827.

ABSTRACT
We develop a procedure to characterize the association of protein structures into homodimers using coevolutionary couplings extracted from Direct Coupling Analysis (DCA) in combination with Structure Based Models (SBM). Identification of dimerization contacts using DCA is more challenging than intradomain contacts since direct couplings are mixed with monomeric contacts. Therefore a systematic way to extract dimerization signals has been elusive. We provide evidence that the prediction of homodimeric complexes is possible with high accuracy for all the cases we studied which have rich sequence information. For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively. This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation. The identification of dimeric complexes can provide interesting molecular insights in the construction of large oligomeric complexes and be useful in the study of aggregation related diseases like Alzheimer's or Parkinson's.

No MeSH data available.


Related in: MedlinePlus

Inferring dimerization complexes with coevolutionary pairings.(A) Two monomeric structures of the tRNA methyltransferase are used in a molecular dynamics simulation that brings the molecules together until reaching a stable complex close to the native homodimer state (shown in the center with light colors). (B) Accurate complex formation is driven by the dimeric constraints (shown in green) extracted using DCA. This methodology seems robust to the existence of those non-dimeric contacts that are used as constrains from DCA. (C) The RMSD progression of the simulation shows how at different stages of the protocol (shown in different background colors) the procedure gets closer to the native structure. At each stage the equilibrium distance and the shape of the Gaussian function are parameterized (See Supplementary Methods) to facilitate the satisfiability of the DCA couplings. For example, the contact range starts at 50 Å and concludes at typical native distances of 8 Å. This figure is representative of all the systems investigated here. For other RMSD progression plots refer to Supplementary Fig. S1.
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f1: Inferring dimerization complexes with coevolutionary pairings.(A) Two monomeric structures of the tRNA methyltransferase are used in a molecular dynamics simulation that brings the molecules together until reaching a stable complex close to the native homodimer state (shown in the center with light colors). (B) Accurate complex formation is driven by the dimeric constraints (shown in green) extracted using DCA. This methodology seems robust to the existence of those non-dimeric contacts that are used as constrains from DCA. (C) The RMSD progression of the simulation shows how at different stages of the protocol (shown in different background colors) the procedure gets closer to the native structure. At each stage the equilibrium distance and the shape of the Gaussian function are parameterized (See Supplementary Methods) to facilitate the satisfiability of the DCA couplings. For example, the contact range starts at 50 Å and concludes at typical native distances of 8 Å. This figure is representative of all the systems investigated here. For other RMSD progression plots refer to Supplementary Fig. S1.

Mentions: The key idea to study residue-residue coevolution involved in dimerization is the combination of accurate prediction of residue contacts using DCA with the availability of monomeric structural data (e.g. X-ray crystallography or NMR). This provides a natural filter for residue pairs that are highly coupled but are found in the hydrophobic core of the protein. These direct couplings are most probably pairings required for folding and not for complex formation. Therefore, we exclude highly coupled pairs that have low surface accessibility as well as those pairs that are in close proximity in the monomeric contact map. Although there exist dimeric contacts that are both monomeric and dimeric, filtering them appears to have a small effect on the complex prediction accuracy. The resulting contacts are then incorporated in a coarse-grained (Cα) SBM with Gaussian potentials45 for complex formation. Figure 1 shows a summary of this methodology exemplified by the tRNA methyltransferase dimer. The residue-residue contacts obtained from coevolution bring the two molecules together after an annealing-like procedure needed for a controlled interfacial reordering and binding. Figure 1B shows the most accurate predicted complex with a lowest RMSD value of 1.5 Å and Fig. 1C shows the RMSD progression until reaching a stable complex close to the native state. The details on how to extract coevolving dimeric signatures and a description of the parameters used in the binding simulations are described in the Methods section and Supplementary Methods.


Dimeric interactions and complex formation using direct coevolutionary couplings.

dos Santos RN, Morcos F, Jana B, Andricopulo AD, Onuchic JN - Sci Rep (2015)

Inferring dimerization complexes with coevolutionary pairings.(A) Two monomeric structures of the tRNA methyltransferase are used in a molecular dynamics simulation that brings the molecules together until reaching a stable complex close to the native homodimer state (shown in the center with light colors). (B) Accurate complex formation is driven by the dimeric constraints (shown in green) extracted using DCA. This methodology seems robust to the existence of those non-dimeric contacts that are used as constrains from DCA. (C) The RMSD progression of the simulation shows how at different stages of the protocol (shown in different background colors) the procedure gets closer to the native structure. At each stage the equilibrium distance and the shape of the Gaussian function are parameterized (See Supplementary Methods) to facilitate the satisfiability of the DCA couplings. For example, the contact range starts at 50 Å and concludes at typical native distances of 8 Å. This figure is representative of all the systems investigated here. For other RMSD progression plots refer to Supplementary Fig. S1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4559900&req=5

f1: Inferring dimerization complexes with coevolutionary pairings.(A) Two monomeric structures of the tRNA methyltransferase are used in a molecular dynamics simulation that brings the molecules together until reaching a stable complex close to the native homodimer state (shown in the center with light colors). (B) Accurate complex formation is driven by the dimeric constraints (shown in green) extracted using DCA. This methodology seems robust to the existence of those non-dimeric contacts that are used as constrains from DCA. (C) The RMSD progression of the simulation shows how at different stages of the protocol (shown in different background colors) the procedure gets closer to the native structure. At each stage the equilibrium distance and the shape of the Gaussian function are parameterized (See Supplementary Methods) to facilitate the satisfiability of the DCA couplings. For example, the contact range starts at 50 Å and concludes at typical native distances of 8 Å. This figure is representative of all the systems investigated here. For other RMSD progression plots refer to Supplementary Fig. S1.
Mentions: The key idea to study residue-residue coevolution involved in dimerization is the combination of accurate prediction of residue contacts using DCA with the availability of monomeric structural data (e.g. X-ray crystallography or NMR). This provides a natural filter for residue pairs that are highly coupled but are found in the hydrophobic core of the protein. These direct couplings are most probably pairings required for folding and not for complex formation. Therefore, we exclude highly coupled pairs that have low surface accessibility as well as those pairs that are in close proximity in the monomeric contact map. Although there exist dimeric contacts that are both monomeric and dimeric, filtering them appears to have a small effect on the complex prediction accuracy. The resulting contacts are then incorporated in a coarse-grained (Cα) SBM with Gaussian potentials45 for complex formation. Figure 1 shows a summary of this methodology exemplified by the tRNA methyltransferase dimer. The residue-residue contacts obtained from coevolution bring the two molecules together after an annealing-like procedure needed for a controlled interfacial reordering and binding. Figure 1B shows the most accurate predicted complex with a lowest RMSD value of 1.5 Å and Fig. 1C shows the RMSD progression until reaching a stable complex close to the native state. The details on how to extract coevolving dimeric signatures and a description of the parameters used in the binding simulations are described in the Methods section and Supplementary Methods.

Bottom Line: Therefore a systematic way to extract dimerization signals has been elusive.For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively.This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation.

View Article: PubMed Central - PubMed

Affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827.

ABSTRACT
We develop a procedure to characterize the association of protein structures into homodimers using coevolutionary couplings extracted from Direct Coupling Analysis (DCA) in combination with Structure Based Models (SBM). Identification of dimerization contacts using DCA is more challenging than intradomain contacts since direct couplings are mixed with monomeric contacts. Therefore a systematic way to extract dimerization signals has been elusive. We provide evidence that the prediction of homodimeric complexes is possible with high accuracy for all the cases we studied which have rich sequence information. For the most accurate conformations of the structurally diverse dimeric complexes studied the mean and interfacial RMSDs are 1.95Å and 1.44Å, respectively. This methodology is also able to identify distinct dimerization conformations as for the case of the family of response regulators, which dimerize upon activation. The identification of dimeric complexes can provide interesting molecular insights in the construction of large oligomeric complexes and be useful in the study of aggregation related diseases like Alzheimer's or Parkinson's.

No MeSH data available.


Related in: MedlinePlus