Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Encounter Complexes and Dimensionality Reduction in Protein-Protein Association

An outstanding challenge has been to understand the mechanism whereby proteins associate. We report here the results of exhaustively sampling the conformational space in protein-protein association using a physics-based energy function. To explore the energy landscape in the vicinity of the native structure, the nonlinear manifold describing the relative orientation of two solid bodies is projected onto a Euclidean space in which the shape of low energy regions is studied by principal component analysis (PCA). Results show that the energy surface is canyon-like, with a smooth funnel within a two-dimensional subspace capturing over 75% of the total motion. Thus, proteins tend to associate along preferred pathways, similar to sliding of a protein along DNA in the process of protein-DNA recognition (Koskov et al., 2014). As an example, the figure below shows the shape of the energy landscape along the five PCA eigenvectors for the complex of PPAR-γ and RXR-α (PDB code 1K74), starting from the largest eigenvalue v1 to the smallest eigenvalue v5 . The left side (Fig. A) shows the distributions of interface RMSD (IRMSD, green) and energy (cyan) values based on structures generated by the PIPER docking program (Kozakov et al., 2006) functions of the coordinates along the eigenvectors shown on the x-axis. Dark blue diamonds indicate low energy data points used for the PCA. The IRMSD (y-axis in the left column) is given in Å. As shown, the low energy conformations spread out along the eigenvector v 1 , resulting in over 50% of all conformational variation, whereas there are little change along the eigenvector v 5 ,, indicating a narrow energy well. Fig B shows the same as Fig. A, but based on structures generated by the RosettaDock program (Gray eat al., 2003).


    1. Kozakov D, Li K, Hall DR, Beglov D, Zheng J, Vakili P, Schueler-Furman O, Paschalidis I, Clore GM, Vajda S: Encounter complexes and dimensionality reduction in protein-protein association. eLife (2014) 3(e01370.

    2. Kozakov D, Brenke R, Comeau SR, Vajda S: PIPER: An FFT-based protein docking program with pairwise potentials. Proteins (2006) 65(2):392-406.

    3. Gray JJ, Moughon S, Wang C, Schueler-Furman O, Kuhlman B, Rohl CA, Baker D: Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations. J Mol Biol (2003) 331(1):281-299.

Dima Kozakov 1
Pirooz Vakili2
Ioannis Ch. Paschalidis3
Sandor Vajda 1, 4

Department of Biomedical Engineering1
Mechanical Engineering2
Electrical and Computer Engineering3
Boston University
Boston, MA.

Ph: (617) 353-4757
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