# Presentation: 323609

## GTL  Facilities  Computing

***Infrastructure for 21******st****** Century***
*** ******Systems Biology***

**Ed Uberbacher**
**ORNL**
**&**
**Mike Colvin**
**LLNL**

## Ultimate Goal is to Provide Predictive Models of Microbes

- Complete datasets
- Quantitative measurements
- Comprehensive physical characterization:
**Protein expression and interactions**
**Spatial distributions**
**Process kinetics**
**Computational:**
- Automated data analysis and validation
- Automated integration of diverse data sets
- Human and computer-accessible databases
- Molecular, Pathway and cell-level simulations

**The goals require a new synergy between computing and biology****.**

**Ultimate Goal is to Provide Predictive Models of Microbes**

***This goal drives data collection and computing strategy.***

## GTL Biology ParadigmIntegrated Large-Scale Experiment-Computing Cycles

**GTL Biology Paradigm*****Integrated *****Large-Scale Experiment-Computing Cycles**

**Real-Time Analysis**

**Design or Revise Models**

**Large-Scale**
**Data Sets**

**Simulate and**
**Generate Hypotheses**

**Experiment**

## Facility IProduction and Characterization of ProteinsEstimating Microbial Genome Capability

**Computational Analysis**
**Genome analysis of genes, proteins, and operons**
**Metabolic pathways analysis from reference data**
**Protein machines estimate from PM reference data**
**Knowledge Captured**
**Initial annotation of genome**
**Initial perceptions of pathways and processes**
**Recognized machines, function, and homology**
**Novel proteins/machines (including ****prioritization)**
**Production conditions and experience**

## Analysis and Modeling
Mass spectrometry expression analysis
Metabolic and regulatory pathway / network analysis and modeling

Knowledge Captured
Expression data and conditions
Novel pathways and processes
Functional inferences about novel proteins/machines
Genome super annotation: regulation, function, and processes (deep knowledge about cellular subsystems)

**Analysis and Modeling**
**Mass spectrometry expression analysis**
**Metabolic and regulatory pathway / network analysis and modeling**
**Knowledge Captured**
**Expression data and conditions**
**Novel pathways and processes**
**Functional inferences about novel proteins/machines**
**Genome super annotation: regulation, function, and processes (deep knowledge about cellular subsystems)**

**Facility II: ****Whole Proteome Analysis****Modeling Proteome Expression, Regulation, and Pathways**

## Regulatory Gene Network Model for Endomesoderm Specification

**Regulatory Gene Network Model for Endomesoderm Specification**

**Eric Davidson**

## Facility III: Characterization and Imaging of Molecular MachinesExploring Molecular Machine Geometry and Dynamics

**Facility III: ****Characterization and Imaging of Molecular Machines****Exploring Molecular Machine Geometry and Dynamics**

**Computational Analysis, Modeling and Simulation**
**Image analysis/cryoelectron microscopy**
**Protein interaction analysis/mass spec**
**Machine geometry and docking modeling**
**Machine biophysical dynamic simulation**
**Knowledge Captured**
**Machine composition, organization, geometry, assembly and disassembly**
**Component docking and dynamic simulations of machines**

## Example of Combined Experiment and Modeling to Understand a Multiprotein Complex: DNA Clamps & Clamp-Loading Mechanisms

**Classical Mol. Dynamics**
- Jeruzalmi et al. *Cell* 106:417 (2001)

**Mechanistic model based on physical and biochemical data **Jeruzalmi et al. *Cell* 106:429 (2001)

**Electron microscopy **Mayanagi et al. J. Struct. Bio. **134: **35 (2001)

**Homology Modeling **Venclovas et al. *Prot. Sci. ***11**:2403 (2002)

**Atomic Force Microscopy**
- Shiomi, et al. *PNAS*, **97:**14127 (2002)

**Example of Combined Experiment and Modeling to Understand a Multiprotein Complex: ****DNA Clamps & Clamp-Loading Mechanisms**

## Facility IV: Analysis and Modeling of Cellular Systems Simulating Cell and Community Dynamics

**Facility IV: ****Analysis and Modeling of Cellular Systems**** ****Simulating Cell and Community Dynamics**

**Analysis, Modeling and Simulation**
**Couple knowledge of pathways, networks, and machines to generate an understanding of cellular and multi-cellular systems**
**Metabolism, regulation, and machine simulation**
**Cell and multicell modeling and flux visualization**
**Knowledge Captured**
**Cell and community measurement data sets**
**Protein machine assembly time-course data sets**
**Dynamic models and simulations of cell processes**

## Centrally Planned Analysis and Modeling Tools Libraries

**Facility 1**
- genome annotation
- regulatory element and operon identification
- metabolic pathway analysis
**Facility 2**
- mass spec data analysis
- expression analysis and clustering
- metabolic and regulatory network modeling
**Facility 3**
- image analysis
- mass spec analysis
- protein / machine modeling
- docking and molecular dynamics
**Facility 4**
- metabolic simulation
- regulatory simulation
- cell modeling and simulations

** ****Collect and manage software**
-  - Maintain current versions
-  - Ensure hardware compatability
-  - User Interfaces
-  - Documentation

**Centrally Planned Analysis and Modeling Tools Libraries**

## GTL facilities will Require High Performance Computing for Both Capacity and Capability

**ATCGTAGCAATCGACCGT...**
**CGGCTATAGCCGTTACCG...**
**TTATGCTATCCATAATCGA...**
**GGCTTAATCGCATACGAC...**

***Capacity*****:  e.g., High-throughput protein structure predictions**

**Thread onto**
**templates**

**Best**
**match**

***Capability*****:  e.g., Large scale biophysical simulations:**

**Large size and timescale classical simulations**

**Highly accurate quantum mechanical simulations**

**GTL facilities will Require High Performance Computing for Both ****C*****apacity***** and *****Capability***

## GTL High-Performance Computing Roadmap

**GTL High-Performance ****Computing Roadmap**

**Biological Complexity**

**Comparative**
**Genomics**

**Constraint-Based**
**Flexible Docking**

****

****

- 1000 TF
- 100 TF
- 10 TF
- 1 TF*

**Constrained**
** ****rigid**
** ****docking**

**Genome-scale**
** ****protein threading**

**Community metabolic**
** ****regulatory, signaling simulations**

**Molecular machine**
** ****classical simulation**

**Protein machine**
**Interactions**

**Cell, pathway, and network simulation**

**Molecule-based**
**cell simulation**

***Teraflops**

**Current U.S. Computing**

## Swimming in Data: Exploding Need to Capture and Manipulate Data

** ****From Acquisition, Refinement, Reduction and Deposition**

**Across Scales of Space and Time - Petabytes**

## Data Repositories
Genomes, annotation and community ‘genomes’
Expression data and proteome composition
Metabolite and flux data
Metabolic pathways and kinetic parameters
Protein interactions
Protein machines repository - machine composition, function, homology, models
Image data repository
Regulatory network data and models
Cell models repository

Integrated or integrable

Requires development of cross-facilities approach

- Data Repositories
- Genomes, annotation and community ‘genomes’
- Expression data and proteome composition
- Metabolite and flux data
- Metabolic pathways and kinetic parameters
- Protein interactions
- Protein machines repository - machine composition, function, homology, models
- Image data repository
- Regulatory network data and models
- Cell models repository
- Integrated or integrable
- Requires development of cross-facilities approach

- phylogeny

- microbial
- genomes

- protein
- domains

- pathways

- regulatory
- elements

- <footer>

- community
- genomes

- literature

- Metabolic
- models

- Expression

- proteomics

- protein
- machines

- regulatory
- networks

- protein
- structure

**Central Database Planning**

## The GTL Knowledge Base:Integration of Large Datasets is a Precursor to Predictive Modeling

**The GTL Knowledge Base:****Integration of Large Datasets is a Precursor to Predictive Modeling**

- GTL knowledge base will change how information about microbes
-    reaches the community
- Models and simulations will be online
- We will know more and more about systems in each consecutive microbe

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