Structural Bioinformatics

Structural Bioinformatics D. Ritchie, P. Tufféry Paris Nancy BISTRO Strasbourg Lyon Th IFB, Jan. 9, 2015

BISTRO Scien&fic leader: Julie Thompson Technical leader: Valérie Cognat IFB correspondent: Valérie Cognat Web: h@p://bioinfo- bistro.fr Par&cipa&ng ins&tutes: GMGM Géné&que Moléculaire, Génomique, Microbiologie IBMC Ins&tut de Biologie Moléculaire et Cellulaire IBMP Ins&tut de Biologie Moléculaire des Plantes ICube Ins&tut de Ingénierie, Informa&que, Imagérie IGBMC Ins&tut de Géné&que et de Biologie Moléculaire et Cellulaire IPHC Ins&tut Pluridisciplinaire Hubert Curien Exper&se: Bioinforma&cs tools and resources, data mining algorithms, focused on evolu&onary and func&onal analyses in various applica&on domains, including biomedical studies, plants, yeast and bacteria

LORIA Scien&fic leader: Marie- Dominique Devignes Technical leader: Olivier Demengeon IFB correspondent : Marie- Dominique Devignes Web : h@p://bioinfo.loria.fr Par&cipa&ng Teams: Capsid, Orpailleur (INRIA) Exper&se: Protein- protein docking and interac&ons, biological data mining, protein structure alignment, small molecule virtual screening, molecular dynamics, cryo- EM, GPUs; various applica&on domains such as bacterial secre&on systems, GPCRs, plant enzymes, drug side effects, drug reposi&oning

PRABI Scien&fic leader: Raphaël Terreux Technical leader: Gilbert Deléage IFB correspondent : Raphaël Terreux Web : h@ps://www.prabi.ibcp.fr Par&cipa&ng Teams: IBCP - Ins&tut de Biologie et Chimie des Protéines (UMR N 5086) Exper&se: Drugs, Pep&des & Protein Design ; Structural Bioinforma&cs of proteins - Large scale automa&c homology modelling of protein. - Large scale comparisons of surface of proteins. - Genera&on of library of organic compound and pep&des : 2D/3D, ADMET predic&on. - Drugs / pep&de - protein interac&ons, Docking, de novo design. - Molecular Dynamics of large system.

RPBS Scien&fic leader: Pierre Tufféry Technical leader: Julien Rey IFB correspondent: Julien Rey Web: bioserv.rpbs.univ- paris- diderot.fr Par&cipa&ng Teams: MTi (INSERM UMR- S 973 Université Paris- Diderot) IMPMC (CNRS UMR 7590 - Université P. et M. Curie) IbiTec- S (CEA - Saclay) CNAM- STIC (CNAM) ABI (Université P. et M. Curie) DSIMB (INSERM U665 Université Paris- Diderot) Exper&se: Structural Bioinforma&cs of proteins; Drugs & Pep&des Design Protein structure and func&on analysis. Compara&ve modeling. Folding nucleus. 3D similari&es. Protein- protein interac&ons. Small compounds: 2D/3D, ADME/tox, focused libraries, ippis, pharmacological profiling, systems toxicology, screening. Pep&des: de novo structure predic&on, protein- pep&de docking, bacterial pep&des. Various applica&ons to cancer, cardiovascular, rare diseases.

Structural Bioinformatics

Structural Bioinformatics DNA Proteins Molecular dynamics Macromolecular assemblies RNA Binding affinity, specificity Molecular structure Chemicals Amino acid variations Solvent, Membranes Peptides Aileron therapeutics

Structural Bioinformatics As A Service @ IFB Focusing on platform skills Molecular dynamics Proteins Macromolecular assemblies Molecular structure Amino acid variations Chemicals Peptides Aileron therapeutics

Structural Bioinformatics As A Service @ IFB De novo structure prediction: Hazardous when > 100 aas. Service vs Research Simulation cost heavy (too for IFB?) Molecular dynamics De novo dimer complex: ~60% success only Proteins Macromolecular assemblies Molecular structure Ranking / scoring: not OK Amino acid variations Chemicals Peptides Aileron therapeutics

Structural Bioinformatics As A Service @ IFB 2015 priorities: 1. Large scale flexible and integrative modeling 2. Modeling protein complexes 3. Assist search for candidate drugs

Structural Bioinformatics As A Service @ IFB Task1:Large scale flexible and integrative modeling BISTRO: Automatic, high quality multiple sequence alignment Clustalw/Omega, DbClustal, ClusPack, RASCAL, LEON, Secator, NorMD, MACSIMS Flexible workflow for classical sequence homology analysis Bayesian statistics for sequence alignments (SIBIS) (IA BipBip) Work plan 2015 01 2015 07 2016 01 PRABI: Comparative modeling and comparisons of whole protein genome. NPS@, Geno3D Compara&ve modeling Hhalign-kbest De novo modeling PEP-FOLD (5-50 aas) Model refinement (Gromacs) Hybrid modeling (linkers,...) (IA BipBip) RPBS: Modeling at low sequence identity.

Structural Bioinformatics As A Service @ IFB Task2: Modeling protein complexes RPBS: De novo complex modeling LORIA: Template based complex modeling Work plan KBDock, Kpax, Hex 2015 01 Scoring complexes using co-evolution (InterEvScore) Template based complexes KBDock + Kpax Pair-wise protein docking (Hex, Piper, Zdock) Refinement: interface to RosettaDock BCSearch 2015 07 Multiple alignment of interologs (InterEvolAlign) De novo binding site candidates (InterEvScore + Hex, Zdock) 2016 01 Considering alternative conformations (BCSearch)

Structural Bioinformatics As A Service @ IFB Task3: Assist search for candidate drugs RPBS: Small compounds u u u 2D/3D generation ADME/tox libraries On-line screening u u u 3D model Candidate protein binding site Docking Peptides Work plan 2015 01 2015 07 2016 01 PRABI: Similar sites in proteins (SuMo) Determined cross allergy reaction

Structural Bioinformatics As A Service @ IFB Miscellaneous tools (Contributed by all sites) Interactive on-line visualization Java based (Jmol, jalview) Javascript based (PV,JSmol) Data formats, Interconversion tools (open-babel, squiz,...) Structure analysis / edition tools (secondary structure, side chains,...) Data collections Deployment framework (Contributed by all sites) MobyleNet, Galaxy, VREs, Docker,... Interactions with IFB-core (Contributed by all sites)

Structural Bioinformatics A one year perspective @ IFB CDD hiring: Ø BISTRO: Arnaud Kress (IE), 09/01/2014 (18 months) Ø LORIA: Jérémie Bourseau (IE), 11/01/2014 (LORIA) then 04/01/2015 (IFB, 15 months). Ø PRABI: in progress, scheduled for 02/01/2015 Ø RPBS: Marek Vavruša (IE), 11/01/2014 (18 months) Tasks: 1.Large scale flexible and integrative modeling 2.Modeling protein complexes 3.Assist search for candidate drugs Workflows on local platform sites expected ~ ok for mid-2015 for most services Interconnection with IFB-core?

Thank you!