Research ArticleBIOCHEMISTRY

Blind protein structure prediction using accelerated free-energy simulations

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Science Advances  11 Nov 2016:
Vol. 2, no. 11, e1601274
DOI: 10.1126/sciadv.1601274
  • Fig. 1 Hydrophobic core instructive.

    (A) Hydrophobic residues in the native structure of protein G. (B) True native contacts that we seek (green lines) and the many possible hydrophobic contacts that must be considered in searching for the native structure (red lines).

  • Fig. 2 MELD performance in CASP11.

    MELD predictions submitted prospectively are shown in blue. Experimental structures are shown in red. Below the structures are Hubbard plots (cumulative α-carbon accuracy), where each line assesses the quality of one submitted model of the target, and where the blue line is the MELD result. The best predictions are given by “elbows” that pass most closely through the bottom-right corner. (A) MELD predictions of three proteins given only sequence data. (B) MELD prediction of 212-residue target with simulated unassigned NMR data. (C) MELD prediction in the presence and absence of data.

  • Fig. 3 Cluster populations are indicative of success.

    (A) Clustering of all conformations for protein T0816. (A) Conformational clustering occurs most strongly at low replica index (low temperature) and in near-native structures. Circle sizes represent cluster populations. The circle center coordinates denote the average RMSD and average replica index of the structures belonging to that cluster. Unfolded clusters tend to have low population. (B) Summary of top cluster populations for tested T0 targets. The populations converge to a single dominant native-like structure for the three protein targets we tried that were less than 100 residues long. Modeling longer chains did not converge to a single population.

  • Table 1 Summary of NMR-like data provided for Ts targets.
    TargetLengthOligomeric stateNMR peaksPossible contactsReduced
    peaks
    Reduced restraintsDaysRMSD
    Ts7612372386729,210828518368.6
    Ts7631312253711,516693261953.0
    Ts785112310724,00921051045.1
    Ts8002121225119,759489331363.2
    Ts80211839002,01422347572.0
    Ts810113111743,62712931745.3
    Ts81813418732,228149426144.5
    Ts824110?8671,600182365121.8
    Ts8262011253123,959152816811.9
    Ts8322091214617,630274234654.0

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/2/11/e1601274/DC1

    Supplementary Text

    table S1. MELD energies of CASP structures.

    fig. S1. Ab initio folding.

    fig. S2. Ab initio folding guided by contact predictions.

    fig. S3. Ab initio folding guided by an unassigned NMR-like data set.

    fig. S4. Native structure for target T0824.

    fig. S5. Comparison of the average performances of different groups over the targets we tackled.

    fig. S6. Simple two-state folding mechanism.

    fig. S7. Complex folding mechanism.

    fig. S8. Identification of multiple misfolded intermediates for T0769.

    fig. S9. Prediction of a mirror topology.

    fig. S10. When the instructives are sufficiently wrong, MELD will not find the correct native structure.

    References (2941)

  • Supplementary Materials

    This PDF file includes:

    • Supplementary Text
      table S1. MELD energies of CASP structures.
      fig. S1. Ab initio folding.
      fig. S2. Ab initio folding guided by contact predictions.
      fig. S3. Ab initio folding guided by an unassigned NMR-like data set.
      fig. S4. Native structure for target T0824.
      fig. S5. Comparison of the average performances of different groups over the targets we tackled.
    • fig. S6. Simple two-state folding mechanism.
    • fig. S7. Complex folding mechanism.
    • fig. S8. Identification of multiple misfolded intermediates for T0769.
    • fig. S9. Prediction of a mirror topology.
    • fig. S10. When the instructives are sufficiently wrong, MELD will not find the correct native structure.
    • References (2941)

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