Hasup Lee, Seungtaek Sun and Ye-Yeong Park ( Group 6 )
• Protein-Protein interaction is important in biological process such as antigen-antibody interaction and cell-signaling pathway. • Protein-Protein Interaction is mediated by van der waals force, electric force, Hydrophobic interaction, hydrogen bond and other interaction. • Sometimes, interface bound water is playing a key role in Protein-Protein Interaction, stabilizing electric force and making new hydrogen bond. • Therefore, Prediction of interface bound water position is important to understand Protein-Protein Interaction.
<Overall Procedure> • Target proteins Endonuclease colicin – Prediction water position Immunity protein complexes using 3D-RISM - E9-Im9 complex (1emv) - E9-Im2 complex (2wpt) Determination bound water - E2-Im2 complex using MD-Simulation (unsolved structure ) Calculating binding free energy using MM-PBSA Comparing with results of native crystal structure E9-Im2 complex E9-Im9 complex
<Bound water> Native interaction Predicted interaction Native Predicted
Δ G bind ΔΔ G bind (kcal/mol) (kcal/mol) Complex -60.33 0.00 without water Complex with -87.26 -26.93 native water Complex with -96.24 -35.91 predicted water
<Bound water> Native interaction 2.842 2.812 2.856 2.898 2.748 3.384 2.761 3.596 Predicted interaction 3.855 2.772 2.695 2.864 2.586 3.334 2.770 3.634 Native Predicted
Δ G bind ΔΔ G bind (kcal/mol) (kcal/mol) Complex -64.05 0.00 without water Complex with -87.40 -23.35 native water Complex with -85.02 -20.97 predicted water
• It is known that colicin E2 interact with Immunity protein 2. • Colicin E2 sequence was solved but its tertiary structure is unknown – MESKRNKPGKATGKGKPVGDKWLDDAGKDSGAPIPDRIADKLRDKEFK NFDDFRKKFWEEVSKDPDLSKQFKGSNKTNIQKGKAPFARKKDQVGGR ERFELHHDKPISQDGGVYDMNNIRVTTPKRHIDIHRGK • Colicin E2 sequence is similar with colicin E9 sequence (Seq ID: 80%), supposing these tertiary structure is also similar. • Therefore we studied E2-Im2 complex interaction following this procedure (1) Modeling tertiary structure of colicin E2 using GalaxyTBM (2) Modeling E2-Im2 complex structure using GalaxyPPDOCK (3) Predicting interface bound water position using 3D-RISM
<Bound water> Predicted interaction 2.692 2.844 3.471 Predicted
Δ G bind ΔΔ G bind (kcal/mol) (kcal/mol) Complex -49.35 0.00 without water Complex with -57.58 -8.23 predicted water
• We predicted Interface bound water position using 3D-RISM. • Mostly, predicted bound water position is similar with native bound water position. • Bound water molecule stabilize electric force and make hydrogen bound, lowering binding free energy compared with no-bound water complex. • We applied 3D-RISM program for E2-Im2 complex having only sequence information, so we searched bound water, lowering binding free energy for stabilizing electric force.
(1) Mostafa H.Ahmed et al., Bound water at Protein-Protein Interfaces: Partners, Roles and Hydrophobic Bubbles as a Conserved Motif , Plos one 2011; 6 , e24712. (2) Kuhlmann U., Pommer A., Moore G., James R. and Kleanthous C., Specificity in Protein-Protein Interaction: The structural Basis for Dual Recognition in Endonuclease Colicin-Immunity Protein Complexes, J. Mol. Biol. 2000; 301 , pp. 1163-1178. (3) Meenan A. et al., The structural and energetic basis for high selectivity in a high-affinity protein-protein interaction, Prot. Natl. Acad. Sci. 2010; 107 , pp.10080-10085. (4) Imai T., Hiraoka R., Kovalenko A. and Hirata F., Locating Missing Water Molecules in Protein cavities by the Three-Dimensional Reference Interaction Site Model Theory of Molecular Solvation, Proteins 2007; 66 , pp.804-813. (5) Sindhikara D., Yoshida N. and Hirata F., Algorithm for accurate prediction of explicit solvent atom distribution: application to HIV-1 protease and F- ATP synthase, In preparation.
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