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. 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:
- 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.
Screen saver/Graphics: When I look at the screen saver image, what is my computer working on?
Your computer is working on a specific protein-protein interactions from the many proteins whose structures are known, with particular focus on those proteins that play a role in neuromuscular diseases. The database of information produced will help researchers design molecules to inhibit or enhance binding of particular macromolecules, hopefully leading to better treatments for muscular dystrophy and other neuromuscular diseases.
Screen saver/Graphics: Why are there two color molecules?
This is to represent the two different proteins that are being calculated for interactions. The positions they are in represent how they are being calculated against each other throughout the work unit.
Screen saver/Graphics: What does the Progress Bar represent?
The Progress Bar represents your computers progress on the specific work unit running on your computer.
Screen saver/Graphics: What do the Erelec and Etmin mean in the circle at the upper left of the graphics window?
The aim of the docking process is to find the best way to associate 2 proteins in order to form a protein-protein complex (and see whether these two proteins are likely to interact, should they ever meet in the "real world", i.e. in a biological system). The quality of the protein-protein interaction can be evaluated via an interaction energy Etmin (expressed in kcal/mol). Erelec is the electrostatic contribution of the interaction energy, which depends on the electric charges that are located all over the protein. The more negative the Etmin is, the stronger the protein-protein interaction.
Please see the following reference for more details on how the interaction energy between two protein is calculated : M. Zacharias, Protein-protein docking with a reduced protein model accounting for side-chain flexibility, Protein Science 12,1271 (2003).
Screen saver/Graphics: What do the two names in the bottom left circle represent?
These are the names of the two molecules that are rotating in the large circle on the screen saver. These two molecules are what your machine is currently calculating.
Screen saver/Graphics: What is UPMC?
Screen saver/Graphics: What does the number 2 behind the name Help Cure Muscular Dystrophy represent?
This indicates that we are currently running Phase 2 of he Help Cure Muscular Dystrophy project. For information about Phase 2, please click here.
Screen saver/Graphics: Who are the people pictured in the slideshow image in the World Community Grid client when Help Cure Muscular Dystrophy - Phase 2 is running?
From left to right:
- Yann Ponty - Postdoc at Laboratoire d'Informatique de Paris 6, CNRS-UPMC, Postdoc AFM/CNRS in 2008, Analysis of data from phase 1, interface between JET and MAXDo and criteria for protein partnership prediction
- Dr. Alessandra Carbone, Analytical Genomics, FRE3214 CNRS-UPMC, Université Pierre et Marie Curie, Paris
- Stefan Engelen - IR Genoscope, Evry, Postdoc AFM in 2006-2008, Prediction of protein binding sites and development of JET
- Sophie Sacquin-Mora, Laboratory of theoretical biochemistry, CNRS Laboratory UPR9080, "Institut de Biologie Physico-Chimique", Paris
What is the difference between Help Cure Muscular Dystrophy Phase 1 and Phase 2?
Phase 1 of Help Cure Muscular Dystrophy ended in June of 2007. The scientists analyzed the results in preparation for Phase 2. The analysis documented and is available at http://www.ihes.fr/~carbone/HCMDproject.htm.