Predicting protein-protein interactions on a proteome scale by matching evolutionary and structural similarities at interfaces using PRISM

Journal name:
Nature Protocols
Year published:
Published online


Prediction of protein-protein interactions at the structural level on the proteome scale is important because it allows prediction of protein function, helps drug discovery and takes steps toward genome-wide structural systems biology. We provide a protocol (termed PRISM, protein interactions by structural matching) for large-scale prediction of protein-protein interactions and assembly of protein complex structures. The method consists of two components: rigid-body structural comparisons of target proteins to known template protein-protein interfaces and flexible refinement using a docking energy function. The PRISM rationale follows our observation that globally different protein structures can interact via similar architectural motifs. PRISM predicts binding residues by using structural similarity and evolutionary conservation of putative binding residue 'hot spots'. Ultimately, PRISM could help to construct cellular pathways and functional, proteome-scale annotation. PRISM is implemented in Python and runs in a UNIX environment. The program accepts Protein Data Bank–formatted protein structures and is available at

At a glance


  1. Description of the prediction algorithm.
    Figure 1: Description of the prediction algorithm.

    (a) Schematic illustration of the concept of the prediction algorithm. If complementary partners (IL and IR) of a template interface are similar to surface regions of any two targets (TL and TR), these two targets can interact with each other via these regions. The red points are hot spots. These incorporate evolutionary information into the matching. (b) The flowchart of the algorithm. There are two data sets in the algorithm: the template data set and the target data set. First, the surface of the proteins in the target data set is extracted. Next, each partner of the template interface is aligned with the target surfaces. If the match passes the residue and hot spot matching thresholds, these targets are transformed on the template interface. If there are colliding residues (e.g., atoms of the residues penetrate into each other's van der Waals radii after they are transformed onto the corresponding template interface) between the two partner targets, the putative complexes are eliminated. Otherwise, the predicted complexes are flexibly refined with their global energies computed. The best solution is chosen as the one with the lowest energy value.

  2. The putative Falcipain-Cystatin complex predicted by PRISM using template 1stfEI.
    Figure 2: The putative Falcipain-Cystatin complex predicted by PRISM using template 1stfEI.
  3. The putative Chk1-p16ink complex predicted by PRISM using templates 1blxAB and 1fmaDE.
    Figure 3: The putative Chk1-p16ink complex predicted by PRISM using templates 1blxAB and 1fmaDE.

    Template interfaces are represented by balls to show the matching parts of the target surface with the template interface partners.


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Author information


  1. Center for Computational Biology and Bioinformatics, College of Engineering, Koc University, Rumelifeneri Yolu, Sariyer Istanbul, Turkey.

    • Nurcan Tuncbag,
    • Attila Gursoy &
    • Ozlem Keskin
  2. Basic Science Program, SAIC-Frederick Inc., Center for Cancer Research Nanobiology Program, NCI-Frederick, Frederick, Maryland, USA.

    • Ruth Nussinov
  3. Department of Human Genetics and Molecular Medicine, Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

    • Ruth Nussinov


A.G. and O.K. developed the initial PRISM concept. N.T., A.G., R.N. and O.K. contributed substantially to the design and implementation of the current flexible PRISM. N.T. did coding and wrote the initial manuscript. All authors contributed substantially to the discussion of the results and to the writing of the paper.

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The authors declare no competing financial interests.

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