STRUCTURAL BIOLOGY AND RADIOBIOLOGY LAB I2BC - CEA Saclay PROTEIN - PowerPoint PPT Presentation

EXPLORING STRUCTURAL INTERACTOMES IN THE LIGHT OF EVOLUTION Jessica ANDREANI Raphaël GUEROIS Molecular Assemblies and Genome Integrity team STRUCTURAL BIOLOGY AND RADIOBIOLOGY LAB I2BC - CEA Saclay

PROTEIN INTERACTIONS AT THE HEART OF MOST CELLULAR PROCESSES • The activation/inhibition of cellular pathways rely on synergies and competitions at the binding surfaces of macromolecules • An atomic/residue scale analysis  Steric hindrance or co-association between partners  Specific design of disruptive and compensatory mutants  Design of PPI modulators

FINDING A CORRECT INTERFACE IN THE HAYSTACK OF POSSIBLE ASSEMBLIES Protein A  ?  Protein B PRINCIPLES OF MOLECULAR DOCKING > 10 4 decoys STEP 1: Low resolution step. Coarse-grained rigid body docking Filters EVOLUTIONARY CONSTRAINTS ?? STEP 2: refinement step. ~ 10 clusters Flexibility, atomic details 1 most likely model

C ONSERVATION OF B INDING M ODES DURING THE COURSE OF E VOLUTION Threshold for interface conservation ~ 30% seq. id (Aloy et al JMB 2003)

I S THE E VOLUTIONARY T RACE OF I NTERACTING P ARTNERS U SEFUL TO P REDICT H OW T HEY B IND ? Substitutions in the alignment  Protein B Protein A  Deleterious mutation  Tolerable/Favorable mutation Good model Protein A Protein B ? Bad model

P RINCIPLES IN I NTERFACE C O E VOLUTION : S TATISTICAL A NALYSES  Q UANTIFICATION OF I NTERFACE P LASTICITY Interface contact chain B chain A Res_k Res_i Database of interfaces with structural & evolutionary information ~18,000 non-redundant interfaces Res_i ’ Res_k ’ among which chain A’ chain B’ ~1,000 pairs of interologs Interface contact? Faure, Andreani & Guerois Nucleic Acids Res. (2012) http://biodev.cea.fr/interevol B B’ A’ A Andreani, Faure & Guerois DECEMBER 11, 2017 DECEMBER 11, 2017 PLoS Comp Biol (2012)

P RINCIPLES IN I NTERFACE C O E VOLUTION : S TATISTICAL A NALYSES  F EATURE E XTRACTION  D OCKING SCORE InterEvScore : Discriminate co-evolved interfaces Apolar Database of Multi-body patches statistical potential interfaces with structural & evolutionary information B A Evolutionary information ≥ 10 sequences Andreani, Faure & Guerois PLoS Comp Biol (2012) Bioinformatics (2013) DECEMBER 11, 2017 DECEMBER 11, 2017

Development of InterEvScore, a docking score taking evolution into account Contact propensities Inter-molecular interface contacts derived from InterEvol (every pair or triplet) (statistics on 1,289 interfaces) 0.53 A B 0.04 -0.05 -0.26 -0.11 Find the most favorable environment for each residue… Residue

Development of InterEvScore, a docking score taking evolution into account Contact propensities derived from InterEvol Inter-molecular interface contacts (statistics on 1,289 interfaces) j i 0.53 A B 0.04 -0.05 -0.26 -0.11 Find the most favorable …and take evolution into account environment for each residue… Residue Alignment for A Alignment for B j i H. sapiens 0.53 M. musculus + 0.53 D. rerio + 0.53 + 0.03 … + -0.20 ≥ 10 sequences S. cerevisiae + 0.53 1.95

I NTER E V D OCK SERVER TO ACCOUNT FOR C O - EVOLUTION I NFORMATION IN D OCKING Structure A Structure B Co-Alignment A Co-Alignment B Returns 10 models (~1h) selected from a consensus among the top solutions of : • InterEvScore (residue based / coevolution), • SOAP-PP (statistical atomic based) ( A. Sali’s lab ), • FRODOCK (rigid-body + physics based) ( P. Chacon’s lab ) Yu et al, Nucleic Acids Research (2016) Running at RPBS server (coll. P. Tufféry) http://bioserv.rpbs.univ-paris-diderot.fr/services/InterEvDock/

I NTER E V D OCK : A S ERVER FOR P ROTEIN R IGID -B ODY D OCKING AND S CORING USING E VOLUTION Performance for 43 rigid-body docking cases from the Weng database for which evolutionary information can be gathered 60 Top10 50 success Structure A rate 40 (%) Structure B 30 Co-Alignment A 20 Co-Alignment B 10 0 InterEvScore FRODOCK InterEvDock SOAP-PP ZDOCK 3.0.2 (v1) consensus 100 % 0 % Average % of interface implication Yu et al, NAR 2016 among Top10 models

P REDICTOR GROUP PERFORMANCE BASED ON THE THREE MOST RECENT CAPRI EVALUATION MEETINGS . Kozakov D et al (2017) Nat. Protocols

H OW TO GET A H IGHER N UMBER OF T ARGETS ? PPI4DOCK : A B ENCHMARK FOR L ARGE S CALE D OCKING A SSESSMENT B ASED ON C OMPARATIVE M ODELS Search for unbound B’ A’ templates Bound A Bound B Reference complex MODELS of A MODELS of B Based on A’ Based on B’ = Unbound A = Unbound B PPI4DOCK contains 1417 docking targets http://biodev.cea.fr/interevol/ppi4dock/ • Ensure MODELS represent unbiased unbound state. • 822 docking targets can be used with coevolution information • Success rate by Rigid-Body docking methods with these MODELS ? Yu & Guerois, Bioinformatics (2017)

Acknowledgements Seydou Arun Chloé Raphaël Françoise Gwenaelle Laure Traoré Nadaradjane Quignot Guerois Ochsenbein Moal Plancon-Arnould May Danni Fouad Nadège Jinchao Bakail Liu Ouasti Guinot Yu I. Jacques Monod Structural Biology and U. Paris 7 I2BC Alessandro Berto Radiobiology Lab Julien Rey Arnaud Martel Valérie Doye Pierre Tufféry