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Human Proteome Folding continues to yield important data for disease

research

By Bonneau, Assistant Professor, Biology and Computer Science

Departments,

New York University, Center for Comparative Functional Genomics

Work on the first phase of the Human Proteome Folding project is drawing to

a close. Nearly all the calculations on World Community Grid are complete,

and a team of researchers at the Institute for Systems Biology (ISB) is now

working around the clock (partly due to the fact that the project involves

researchers around the globe, and partly due to our drive to publish) to

process the results and get them out to other researchers and the volunteer

community that contributed so greatly to this project.

Our first publication of results will center on a model-organism -- yeast.

Yeast has been a widely studied organism for over a century and due to this

and the ease of working with yeast it has become a work-horse in biology.

Much of what we know about molecular biology and the function of proteins

was first discovered in yeast. For this reason yeast is called a

" model-organism. "

After we have debugged the process using yeast we will quickly release the

remaining 100 organisms folded during the project. These databases will

contain sequence-based analysis of the proteins, predictions about how the

proteins are organized into domains, and structure and function predictions

for the protein domains folded as part of this project.

While all this is going on, IBM is helping us to further model an important

subset of the proteins as part of a second phase of the project that also

will run on World Community Grid.

Phase Two

The proposed second phase of the Human Proteome Folding project will launch

on World Community Grid in April 2006. The two main objectives are to: 1)

obtain higher resolution structures for specific human proteins and pathogen

proteins and 2) further explore the limits of protein structure prediction

by further developing Rosetta software structure prediction. Thus, the

project will address two very important parallel imperatives, one biological

and one biophysical.

The project will refine, using Rosetta software in a mode that accounts for

greater atomic detail, the structures resulting from the first phase of the

project. During the first phase, we aimed to understand protein function.

During the second phase, our goal is to increase the resolution of a select

subset of human proteins. Better resolution is important for a number of

applications, including but not limited to virtual screening of drug targets

with docking procedures and protein design. The second phase of the project

also will serve to improve our understanding of the physics of protein

structure and advance the state of the art in protein structure prediction

(helping us to further develop our program, Rosetta).

The project will focus on human-secreted proteins (proteins in the blood and

the spaces between cells). These proteins can be important for signaling

between cells and are often key markers for diagnosis. These proteins have

even ended up being useful as drugs (when synthesized and given by doctors

to people lacking the proteins). The simplest example of a human secreted

protein turned into a therapeutic is insulin; another example is human

growth hormone. Understanding the function of human secreted proteins may

help researchers discover the function of proteins of unknown function in

the blood.

The project also will focus on key secreted pathogenic proteins. We are

still in the early design phases of this part of the project, but we will

likely focus on Plasmodium, the pathogenic agent that causes malaria. We

hope that higher resolution structure predictions for the proteins that

malaria secretes will serve as bioinformatics infrastructure for researchers

who are working hard around the world to understand the complex interaction

between human hosts and malaria parasites. While there are few silver

bullets, and biology is one of the most complicated subjects on earth, we

believe that this work will help us understand elements of this

host-pathogen interaction or at least its components. This understanding

could then be a foundation for intervention.

Lastly, this project dovetails with efforts at the ISB to support

predictive, preventative and personalized medicine (under the assumption

that these secreted proteins will be key elements of this medicine of the

future). It is too early to say which proteins will end up being biomarkers,

which are substances sometimes found in an increased amount in the blood,

other body fluids, or tissues and which can be used to indicate the presence

of some types of cancer. However, it is clear that many will end up being

secreted proteins. As in the first phase of the project, the power of World

Community Grid will be critical in getting results quickly to researchers in

the biological and biomedical communities.