Course Review Name one important thing that you learnt from this course that you feel will be important to your research career Name one aspect you were hoping to learn that you did not Pharm 201 Lecture 19, 20111

2 Some Thoughts on the Future of Biological Data with Emphasis on Structural Bioinformatics Philip E. Bourne Dept. of Pharmacology University of California San Diego

Pharm 201 Lecture 19, Agenda What is structural genomics and what is its impact? Unsolved problems in structural bioinformatics New challenges related to structural bioinformatics The bigger picture The final

Pharm 201 Lecture 19, Structural Genomics: A Broad Working Definition Structural genomics is the process of high- throughput determination of the 3- dimensional structures of biological macromolecules

Pharm 201 Lecture 19, SG - What is the Goal? The goal of the human genome project was clear cut.. The goal of structural genomics is not so clear cut Phase I.. –Provision of enough structural templates to facilitate homology modeling of most proteins –Structures of all proteins in a complete proteome –Structural elucidation of a complete biological pathway –Structural elucidation of a complete disease

Pharm 201 Lecture 19, Example Goals (Phase I) “The hyperthermophilic bacterium Thermotoga maritima has been the target of choice for pipeline development and genome-wide fold coverage.“ Thermotoga maritima “The SGPP consortium will determine and analyze the three-dimensional structures of a large number of proteins from major global pathogenic protozoa, Leishmania major, Trypanosoma brucei, Trypanosoma cruzi and Plasmodium falciparum. “Leishmania major Trypanosoma bruceiTrypanosoma cruziPlasmodium falciparum “It is aimed at determining structures of proteins and protein complexes directly relevant to human health and diseases. “ Structural Genomics of Pathogenic Protozoa

Pharm 201 Lecture 19, Growth in the Number of New Topologies per Year According To CATH Total Folds New Folds from Nov., rowthChart.do?content=fold-cath SG Had Very Little Direct Impact on New Folds and Hence Homology Modeling

Pharm 201 Lecture 19, SG - What is the Goal? – Phase II

SG – Phase III – PSI-Biology The third phase of the PSI is called PSI:Biology and is intended to reflect the emphasis on the biological relevance of the work Pharm 201 Lecture 19,

Implications of Phase III SG Less single domains more complex structures More p-p complexes More protein-ligand complexes More membrane proteins Better models More hybrid structures More molecular machines Pharm 201 Lecture 19,

SG Accounts for 14% of Structures Pharm 201 Lecture 19, From RCSB PDB Nov 2011

Pharm 201 Lecture 19, Agenda What is structural genomics and what is its impact? Unsolved problems in structural bioinformatics New challenges related to structural bioinformatics The bigger picture The final

Crude Estimators of What We Know and How We Might Get Better - Basics Data accessibility (60%) Domain definitions (80%) Structure comparison (80%) Disorder predictors (70%) Structure classification (80%) Need more computer accessible information on function etc. Need fresh approaches Need a better understanding of the role of protein disorder period More quantitative approaches Pharm 201 Lecture 19,

Crude Estimators of What We Know and How We Might Get Better Basic knowledge of macromolecular structure (50%) PPI’s Protein-ligand interactions ligand view (30%) Integrated view of structure as part of a biological continuum of data and associated knowledge (30%) Structure prediction from sequence (40%) Missing temporal view, alternative views Missing robust rules for molecular recognition Need better quantification Need more structures Pharm 201 Lecture 19,

Crude Estimators of What We Know and How We Might Get Better Inferring function from structure (40%) Macromolecular assemblies (40%) Docking (30%) Rational drug discovery (10%) Evolution (10%) A combination of improvements Hybrid methods Better scoring, flexible docking, allostery Polypharmacology, network pharmacology Accurate proteome coverage Pharm 201 Lecture 19,

Natalie Dawson Unpublished 16Pharm 201 Lecture 19, 2011 Example 0f What Could be Done in Evolution: Structural Domains and the Tree of Life

Pharm 201 Lecture 19, Example 0f What Could be Done in Evolution: Structural Domains and the Tree of Life

18 Example: Structural Mapping and Subsequent Insights from All Biochemical Pathways Pharm 201 Lecture 19, 2011

Tykerb – Breast cancer Gleevac – Leukemia, GI cancers Nexavar – Kidney and liver cancer Staurosporine – natural product – alkaloid – uses many e.g., antifungal antihypertensive Collins and Workman 2006 Nature Chemical Biology Example: Better Understanding of Drug Receptor Interactions 19

Pharm 201 Lecture 19, Agenda What is structural genomics and what is its impact? Unsolved problems in structural bioinformatics New challenges related to structural bioinformatics The bigger picture The final

New Challenges Effective use of structural information in systems biology – eg structural ppis Bridging the biological scales in an easily understood way New ways of visualizing and hence thinking about proteins Protein design/engineering Pharm 201 Lecture 19,

Pharm 201 Lecture 19, Agenda What is structural genomics and what is its impact? Unsolved problems in structural bioinformatics New challenges related to structural bioinformatics The bigger picture The final

The Bigger Picture - Numbers Pharm 201 Lecture 19, On the Future of Genomic Data Science 11 February 2011: vol. 331 no

The Bigger Picture – Accuracy Functional Misannotation Pharm 201 Lecture 19, PLoS Comput Biol (12): e

The Bigger Picture – Data Culture Data are not available Data are undervalued Data are stovepiped This is a long tail of data which are lost Institutional repositories are roach motels Data repositories will go like journals Pharm 201 Lecture 19,

Beyond Data What is Wrong Today? Pharm 201 Lecture 19,

What is Wrong Today? Formal science communication: –Occurs too slowly –Reaches too few people –Costs too much –Ignores the data –Is very hard to reproduce Is stuck in the era of the printing press – we need to move Beyond the PDF and use the power of the medium

Literature DataMethods The Research Enterprise

The Current Reality

Data Knowledge Database Knowledgebase Wikis Datapacks Journals Data Only Data + Some Annotation Data + Some Annotation + Some Integration Data + Annotation PLoS iStructure 30 Pharm 201 Lecture 19, 2011

1. A link brings up figures from the paper 0. Full text of PLoS papers stored in a database 2. Clicking the paper figure retrieves data from the PDB which is analyzed 3. A composite view of journal and database content results My Dream 1.User reads a paper (one view of the info) 2.Clicks on a figure which can be analyzed 3.Clicking the figure gives a composite database + journal view 4.This takes you to yet more papers or databases 4. The composite view has links to pertinent blocks of literature text and back to the PDB The Knowledge and Data Cycle

It Goes Beyond Data Its hard and embarrassing to reproduce your own work We have a working prototype using Wings I can feel the potential productivity gains My students are more doubtful Its been a lot of fun and will enable us to improve our processes regardless of the workflow system itself Literature Data Methods

Yes The Workflow is Real Literature Data Methods

Problems with Publishing Workflows Workflows are not linear Workflow : paper is not 1:1 Confidentiality Peer review Infrastructure Community acceptance Reward system No publisher seems willing to touch them Literature Data Methods

Pharm 201 Lecture 19,

Pharm 201 Lecture 19, Agenda What is structural genomics and what is its impact? Unsolved problems in structural bioinformatics New challenges related to structural bioinformatics The bigger picture The final

The Final Prepare a mini-grant research proposal with the following ingredients: –Background and Significance –Preliminary Results –Proposed Research and Methods –Expected Outcomes The theme is any aspect of the course where you would like to contribute new research ideas and potential outcomes Pharm 201 Lecture 19,

The Final Points (50) will be awarded for: – B&S – literature coverage, justification of the originality and potential importance of the contribution (20) –Pre Res – anything you can actually accomplish to support the proposal eg pseudocode, computations using existing tools, etc. (15) – Proposed Research – the credibility and rigor of what you propose (10) –Expected Outcomes (5) There is no length requirement but I would anticipate ~10, 12pt single space pages to do the topic justice This should not relate to one of your previous assignments Feel free to me to discuss ideas before starting Pharm 201 Lecture 19,