1. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. ARPPI: A knowledge-based model for protein-protein interactions J.-M Yang, L.-S. Chang, and K.-P. Liu Institute of Bioinformatics, National Chiao Tung University, Taiwan R.O.C.

2. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Outline Introduction Material and Method Results Summary Acknowledgment

3. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Introduction The protein-protein interactions are important for many biological functions The protein-protein docking is one of the key to identify these processes The scoring function is critical in protein docking algorithm  Various approaches have been developed Residue level (C β -C β )  Glaser et al. : residue-residue contact preferences  Often poor in hydrogen bond and electrostatic interactions Atom level  Zhang et al. : 18 different atom types  Often Poor in aromatic interactions

4. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Novel views of our model : ARPPI Distance bins : sensitive  Special forces occurred in particular distance 167-atom-type : residue & atom Advantage  Reflect hydrogen bond Donor atom: Asn-OD1, Lys-NZ … Acceptor atom: Asp-OD1, Glu-OE2 …  Reflect electrostatic forces Charge atom : Arg-NH1, Asp-OD1…  Reflect aromatic forces Aromatic atom : Phe-CD1, Trp-CZ3, … (Nature 2004) (http://www.bio.mtu.edu/campbell/401lec9p1c.html) (Nature 2004) Donor-acceptor pairs with particular distance Charged atom pairs with particular distance Aromatic atom pairs with particular distance

5. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Material and Method

6. Residue typeatom typeNumber of atom types Total number of atom types GlyN CA C O O4 167 AlaN CA C O CB O CB5 ValN CA C O CB CG1 CG27 LeuN CA C O CB CG CD1 CD28 IleN CA C O CB CG1 CG2 CD18 MetN CA C O CB CG SD CE8 PheN CA C O CB CG CD1 CD2 CE1 CE2 CZ11 TyrN CA C O CB CG CD1 CD2 CE1 CE2 CZ OH12 TrpN CA C O CB CG CD1 CD2 NE1 CE2 CE3 CZ2 CZ3 CH214 SerN CA C O CB OG6 ProN CA C O CB CG CD7 ThrN CA C O CB OG1 CG27 CysN CA C O CB SG6 AsnN CA C O CB CG OD1 ND28 GlnN CA C O CB CG CD OE1 NE29 LysN CA C O CB CG CD CE NZ9 HisN CA C O CB CG ND1 CD2 CE1 NE210 ArgN CA C O CB CG CD NE CZ NH1 NH211 AspN CA C O CB CG OD1 OD28 GluN CA C O CB CG CD OE1 OE29 Definition of 167-atom-type model

7. 641 protein Complexes (Glaser et al.) GLY N GLY CA … GLU OE2 GLY N 130310214 GLY CA 3109858... GLU OE2 21458107 Observed pairs Summation of every atom-atom pairs for each distance bins GLY N GLY CA … GLU OE2 GLY N 1.53.20.9 GLY CA 3.2-0.5-2.1... GLU OE2 0.9-2.10.2 Interactive scores Boltzmann Distribution Observed atom-atom pairs derived from protein complex SER-C THR-CA SER-C THR-N PRO-CD HIS-CE1 2 3 4 5 Protein complex 1 0.0 3.04.0 6.0 5.0 1234567k Å Bin 1 2 3 4 5 … Statistic of atom-atom pairs with different distance bins SER-C THR-CA PRO-CD HIS-CE1 Bin 2 : Bin 6 : Bin 3 : Bin 7 : Flowchart of ARPPI model Bin 1, 2… K

8. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Results

9. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Atom level : donor-acceptor atom-atom pair interactions vs. interactive scores 3.3Å 2.9Å Glu Arg OE2 NH2 NH1 6.3Å 5.8Å Glu Arg OE2 NH2 NH1 Donor-acceptor Interactions of Hydrogen bond Donor-acceptor Interactions of VDW forces

10. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Atom level : Charged atom-atom pair interactions vs. interactive scores 3.7Å 4.6Å Arg Asp NH2 NH1 OD2 OD1 3.2Å Arg Asp 10.1Å OD2 NH2 Charged atom pair Interacting energy of electrostatic forces Charged atom pair Interacting energy of VDW forces

11. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Residue level : Non-polar atom-atom pair interactions vs. interactive scores 5.3Å 5.8Å Phe Trp Non-polar atom-atom interactions (all to all) Non-polar atom-atom interactions (sidechain to sidechain)

12. The 167x167 atom-atom interaction scoring matrixes at two distance bins: (A) 3.0 Å to 3.5 Å and (B) 3.5 Å to 4.0 Å GLU OE1, OE2 ASP OD1, OD2 GLN OE1 ARG NH1, NH2 HIS NE2 LYS NZ ARG CZ GLU OE1, OE2 ASP OD1, OD2 Hydrogen Bond Disappear Sidechain N Donor Backbone O Acceptor Hydrogen Bond Interactions

13. Bound structuresNumber of Hits c in top 200 rank Complex a ARPPI18 atom type d 20 residue type e A. Enzyme-inhibitor complexes 1fss b 1091360 1mah 861190 1sbn 1621330 1udi b 1561440 1ugh 1851590 2kai b 1581370 2ptc b 1501510 3sic b 1471690 B. Antibody-antigen complexes 1bql 1551360 1jhl b 1491160 2jel b 1581280 3hfl 1601410 3hfm 1641490 C. Other complexes 1atn b 1551360 1gla b 1681380 2mip 1901680 3hhr b 1851780 a 4-letter PDB code for the crystal structures used in this study. b Crystal structure is selected from 641 protein-protein interfaces. c Hits are defined as candidate structures with all main chain atoms RMSD ≦ 2.0 Å from the crystal complex. d All types are defined as Zhang et al. e 20 residue type representation : C α for Gly and C β the other amino acids are considered as the residue center. Total number of best prediction 13 Total number of best prediction 4 Total number of best prediction 0 Native score: -431.6 Native score: -323.5Native score: -187.2 Native structure Top 200 rms = 2 Top 200 rms = 2

14. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Summary ARPPI  Provides information: Atom-atom (hydrogen bonds, electrostatic interactions) Residue-residue (aromatic-aromatic interactions) Distance bins (sensitive)

15. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Acknowledgement National Science Council, Taiwan R.O.C. Structural Bioinformatics Core Facility

16. Copyright © 2007, BioXGEM Lab., Institute of Bioinformatics, NCTU All rights reserved. Thank you for your attention!