What is the Decrypthon Program?
The Decrypthon Program is a collaboration launched by AFM (French Muscular Dystrophy Association), CNRS (French National Center for Scientific Research) and IBM in May 2004 (www.decrypthon.fr). This partnership is a technical platform for grid computing which includes technical, financial, and human resources in which RENATER (French National Communication for Research and Network), Universities, and individual Internet users participate.
The goal of this program is to provide to research groups very high capacity of grid computing resources and technical facilities for shared calculation, in order to facilitate and accelerate the development of research programmes in the field of biology, and in particular in the context of neuromuscular disorders. This program also includes technical support from IBM and CNRS for selected groups for the validation, porting, and gridification of their project, and financial support from AFM to support the project.
What are protein functions?
Proteins are the basis of how biology gets things done:
Since proteins play such fundamental roles in biology, scientists have sequenced the human genome, which is a "blueprint" for these proteins. It contains the DNA code which specifies the sequence of the amino acids, i.e. the elementary bricks that constitute the protein.
- They are the biological elements that catalyze all of the biochemical reactions which make cells work (i.e. the enzymes).
- They are the main structural elements that constitute our bones, muscles, blood vessels, etc.
The challenge of modern biology is to understand what these proteins do and how they work in cells.
What is a protein structure?
Proteins are large molecules made of long chains of basic units: the amino acids. Proteins do not remain as simple amino acids chains, but fold into a more compact and specific shape (3D-structure) that specifies the protein function within the body.
Indeed, the knowledge of the amino acid sequence tells us little about what the protein does and how it does it. In order to perform its function, it must take on a particular shape, also known as a "fold." Thus, to do their work proteins assemble themselves. This self-assembly is called "folding." The process of protein folding, while critical and fundamental to virtually all of biology, in many ways remains a mystery.
The number of shapes that proteins can fold into is enormous in theory, but only one structure corresponds to the proper protein fold found in the human body. Human cells have developed mechanisms to help proteins to fold properly to carry out specific functions within the human body.
Moreover, when proteins do not fold correctly (i.e. "misfold"), they can lead to serious consequences, including many well known diseases such as Alzheimer's, Huntington's, Parkinson's disease, many cancers syndromes, etc.
Information obtained on the structure of those complexes is important not only for identifying functionally important partners, but also for determining how such interactions will be perturbed by natural or engineered site mutations in either of the interacting partners, or as the result of drugs.
What is molecular modeling?
Molecular modeling refers to theoretical methods and computational techniques to model or mimic the behavior of molecules. Molecular modeling methods are used to investigate the structure of biological systems such as protein folding or molecular recognition of protein- ligand binding, ranging from small chemical systems to large biological molecules and material assemblies (protein complexes).
The common feature of molecular modeling techniques is the atomistic level description of the molecular systems; the lowest level of information is individual atoms (or a small group of atoms).
The interactions between neighboring atoms (atoms are the smallest units that form the matter) can be drawn by spring-like interactions (representing chemical bonds). A complex mathematical model which takes into account the sum of potential energies (forces) describes these atomic interactions.
Indeed, for complex structures like proteins (composed of hundred of atoms for the smallest), it takes CPU time to model their 3D-structure.
What is protein-ligand docking?
For most of the proteins known to date, their biological role is incompletely understood. Even proteins which participate in a well-understood biological process may have interaction partners or functions which are unrelated to that process.
Moreover, vast numbers of "hypothetical" proteins have been discovered during the human genome sequence program, for which there is no information at all, apart from their amino acid sequence.
Indeed, for any protein, scientists attempt to answer the questions: does the protein bind in vivo? If it does, what is the 3D-structure of the complex and how strong/weak are the protein-ligand interactions?
Protein-ligand docking is a molecular modeling technique to predict the position and orientation (the 3D-structure) of a protein in relation to a ligand (another protein, DNA, drug, etc.).
Docking methods are based on purely physical principles; even proteins of unknown function (or which have been studied relatively little) may be docked. The only prerequisite is that their 3D-structure has been either determined experimentally, or can be estimated by some theoretical technique.
Docking techniques could be used for a variety of purposes, most notably in the virtual screening of large databases of available chemicals in order to select drug candidates.
Decrypthon Molecular Docking vs. FightAIDS@Home
Since November 2005, World Community Grid has been running FightAIDS@Home (FAAH). This project has been investigating computational ways to design effective, inexpensive drugs that stop the HIV virus, and thus the onset of AIDS.
The Decrypthon and FAAH projects are alike in that they both use computer programs which simulate the docking of two compounds/molecules together to see how well they bind to each other. FAAH is searching through many compounds that bind to a certain portion of an enzyme (a protein) called HIV protease needed by the HIV virus to replicate. If a compound is found that strongly attaches to a certain part of the HIV protease, it prevents it from functioning and thus keeps HIV from replicating.
The Decrypthon project is also docking molecules, but doing this among all of the proteins, genes (DNA), and potential drugs (ligands) that seem to play a role in neuromuscular diseases. This is being done to better understand what specific roles all of these proteins play in both normal and disease processes.
Why does the Help Cure Muscular Dystrophy project only run on Windows?
At the present time, we are only running Phase 1 of the Help Cure Muscular Dystrophy project. Phase 1 has only a relatively small amount of work units but the work is important for analysis in preparation for Phase 2. Phase 2 will be much larger and is scheduled to start later in 2007. Because Phase 1 is very small and will not run very long we decided not to run it on BOINC. This means that the project will not run on the three BOINC platforms: Windows, Linux, and Mac. Phase 1 only runs on UD which is Windows only. Phase 2 will run on both UD and BOINC.