Course Review

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, 2011 1


Some Thoughts on the Future of Biological Data

with Emphasis on Structural Bioinformatics

Philip E. BourneDept. of Pharmacology

University of California San [email protected]


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


Structural Genomics:A Broad Working Definition

Structural genomics is the process of high-throughput determination of the 3-dimensional structures of biological

macromolecules


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


Example Goals (Phase I)“The hyperthermophilic bacterium Thermotoga maritima has been the target of choice for pipeline development and genome-wide fold coverage.“

“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. “

“It is aimed at determining structures of proteins and protein complexes directly relevant to human health and diseases. “

117

1257

70Structural Genomics of Pathogenic Protozoa

http://www.tigr.org/tigr-scripts/CMR2/GenomePage3.spl?database=btm

http://www.sgpp.org/leishmaniasis.shtml

http://www.sgpp.org/african_sleeping_sickness.shtml

http://www.sgpp.org/chagas.shtml

http://www.sgpp.org/malaria.shtml

http://www.jcsg.org/

http://www.sgpp.org/index.shtml


Growth in the Number of New Topologies per Year According To CATH

Total Folds

New Folds

from Nov., 2011

http://www.rcsb.org/pdb/statistics/contentGrowthChart.do?content=fold-cath

SG Had Very Little Direct Impact on New Folds and Hence Homology Modeling




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


http://en.wikipedia.org/wiki/Protein_Structure_Initiative

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


SG Accounts for 14% of Structures


From RCSB PDB Nov 2011


Agenda





• 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


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


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


http://itol.embl.de/

Natalie DawsonUnpublished

16Pharm 201 Lecture 19, 2011

Example 0f What Could be Done in Evolution: Structural Domains and the Tree of Life

http://itol.embl.de/


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 2 689-700

Example: Better Understanding of Drug Receptor Interactions

19


Agenda





• 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



Agenda





• The final

The Bigger Picture - Numbers


On the Future of Genomic DataScience 11 February 2011: vol. 331 no. 6018 728-729

The Bigger Picture – AccuracyFunctional Misannotation


PLoS Comput Biol 2009 5(12): e1000605.

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


Beyond Data What is Wrong Today?


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

https://sites.google.com/site/beyondthepdf/http://www.force11.org

https://sites.google.com/site/beyondthepdf/

Literature

DataMethods

The Research Enterprise

The Current Reality

http://www.flickr.com/photos/51282757@N05/5585299226/lightbox/

Data Knowledge

Database Knowledgebase Wikis Datapacks Journals

Data Only

Data + SomeAnnotation

Annotation

Data + SomeAnnotation

+Some

Integration

Data +Annotation

PLoS iStructure

30Pharm 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 retrievesdata from the PDB which is

analyzed

3. A composite view ofjournal 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 haslinks to pertinent blocks

of literature text and back to the PDB

1.

2.

3.

4.

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

DataMethods

Yes The Workflow is RealLiterature

DataMethods

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

DataMethods



Agenda





• 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


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 email me to discuss ideas before starting


Documents

Course Review