World Community Grid: help cure muscular dystrophy!
Help Cure Muscular Dystrophy – Phase 2: The 14th World Community Grid Project
Distributed Computing Online MagazineHelp Cure Muscular Dystrophy – Phase 2 (Help Cure Muscular Dystrophy – Phase 2) is a distributed computing project launched on May 12, 2009 with the support of the World Community Grid association.
This is a joint study of the partner organization Decrypthon, which includes AFM (French Muscular Dystrophy Association), CNRS (French National Center for Scientific Research), INSERM (French public health organization) and Universite Pierre et Marie Curie (Pierre and Marie Curie University). The aim of the project is to study 2,246 proteins specifically associated with the occurrence of neuromuscular diseases. The information obtained within the framework of the project will be used to develop innovative methods for the treatment of muscular dystrophy and similar diseases.
IntroductionIn 1986, the first gene of the dystrophin protein was identified, mutations in which lead to Duchenne Muscular Dystrophy, the most common form of muscular dystrophy.
Duchenne myodystrophy occurs with a frequency of 3:10,000 live-born boys. Genetically, it belongs to X-linked recessive lethal disorders and is caused by a mutation in the gene responsible for the synthesis of the protein dystrophin, which plays an important role in maintaining the integrity of muscle fiber membranes. As a result of the increased permeability of cell membranes, enzymes, amino acids, carbohydrates, etc. "flow out" of myofibrils, and substances that violate their normal vital activity seep into cells from the intercellular fluid. The death of muscle fibers leads to atrophy of skeletal muscles, and the cause of death (in the second or third decade of life) usually becomes atrophy of the heart muscle.
Thanks to genetic research, more than 200 genes that cause neuromuscular diseases are known today. However, until now, knowledge about the functions and interactions of proteins encoded by these genes remains extremely insignificant. The disclosure of the mechanisms of the origin and development (pathogenesis) of neuromuscular diseases, given the large number of genes involved in it and the proteins encoded by them, becomes an increasingly difficult task as our knowledge in this field increases.
All cells contain the same genetic information in the form of DNA, which as a whole forms the genome of the organism. The process of gene expression (more than 20 thousand genes have been found in humans) contained in the genome leads to the formation of proteins (more than 45 thousand, i.e., on average, one gene encodes 1.6 proteins), without which the functioning of cells, including specific ones, for example, muscle, is impossible. Some of these proteins are enzymes, others are signaling molecules, and may be receptors specifically binding to other molecules (ligands), as well as structural proteins. The conformation (three-dimensional shape) of a protein determines its functions.
The functioning of muscles depends on many proteins. These proteins are localized and work at various levels – in the cell shell, its protoplast (internal contents) or in the axon of the motor nerve, which connects the nerve to the muscle tissue and transmits commands to the nervous system.
Most neuromuscular diseases occur under the influence of genetic changes (mutations in certain genes cause changes in the three-dimensional structure of the protein encoded by them), leading to the loss of proteins in whole or in part of their original functions or to the cessation of protein synthesis as such. Neuromuscular diseases can be classified by proteins or sections of proteins modified by gene mutation.
Therefore, in order to understand the nature of a neuromuscular disease, researchers seek to associate them with a violation of the functionality of certain proteins. A more precise understanding of the interactions and functions of proteins involved in the pathogenesis of a particular muscular dystrophy is needed.
It is impossible to overestimate the importance of this information in the development of therapeutic procedures and innovative methods of treatment of many neuromuscular diseases.
Project objectiveHelp Cure Muscular Dystrophy plans to use a distributed computing network to determine interactions between more than 2,200 proteins with a known structure, information about which is contained in the Protein Data Bank.
Proteins that are synthesized as a result of the expression of mutated genes will also be studied.
The aim of the project is to create a new database with information about functionally interacting proteins. Further research will be related to the study of protein sites involved in the interactions of ligands (for example, drugs) with DNA. This topic is of considerable medical interest, although now the emphasis is on the design of small molecules (ligands) that disrupt (inhibit) or improve the work of certain proteins: it is much more difficult to determine the indirect effects of small molecules on the functions and interactions of proteins).
Research approachThis project uses an approach that combines information about evolution (how development changed proteins and determined their functions) and molecular modeling (determining the relative position of two interacting partner proteins) to identify potential interactions of proteins both with each other and with potential ligands.
Molecular modeling combines theoretical and computational methods to model the behavior of biological molecules. These methods are used to study the three-dimensional structure of biological systems, such as protein globules, or to identify protein ligands binding to small chemical systems, large biomolecules and protein complexes.
Modeling of docking (docking) of a protein and a ligand allows predicting the position and orientation of a protein that has adopted a three-dimensional structure relative to a ligand (which may be another protein, DNA or drug). Molecular docking is based solely on physical principles – even proteins with unknown or poorly understood functions can be examined for docking with various ligands. The only prerequisite is the knowledge of the three-dimensional structure of proteins obtained by theoretical methods or in the course of experimental research.
When using molecular docking, the known molecules are searched from databases in order to search for variants that detect affinity, i.e. they bind well to each other. The degree of affinity is determined using an evaluation function based on the geometric and chemical parameters of the resulting compound. The geometry is evaluated by how well the three-dimensional structures of the protein and ligand are combined: they must be fitted like a hand under a glove. From a chemical point of view, the strength of the interatomic interactions between the protein and the ligand is estimated.
For such complex structures as proteins, the smallest of which contain hundreds of atoms, studies of protein-protein interactions can require significant computational resources. Without the World Community Grid, the calculations needed to simulate molecular docking would be too time-consuming. For the first 168 proteins studied in the first phase of the project, the processor time involved using a distributed computing network was 8,000 years. In the second phase of the project, where 2,246 proteins will already be studied, the estimated calculation time will reach 91,680 years.
To overcome this computational barrier will help information about the evolution of proteins, which allows you to predict the interacting parts of proteins. This preliminary analysis reduces the estimated calculation time by 100 times, thereby increasing the number of proteins studied. However, without the help of volunteers, the planned calculations will be impossible.
Volunteers donating free computing resources to World Community Grid will free up capacity for other research conducted by AFM, CNRS, INSERM, etc. scientific players aimed at developing scientific tools that increase our knowledge about the nature and methods of treating rare diseases.
Connecting to the World Community Grid project as part of the Distributed Computing team RussiaCreate an account on the World Community Grid website, select your favorite research projects (including Help Cure Muscular Dystrophy – Phase 2).
Then download the latest version of the BOINC Manager – it is a universal program for participating in distributed computing. Install and run BOINC. Enter Advanced View mode. Then find the "Add project" item in the "Tools" menu. In the "Project Selection" window that appears, find the World Community Grid in the list of projects. After that, BOINC will prompt you to enter the parameters of your account, which you did a little earlier. The project files will be downloaded, and after its completion, calculations will begin. Visit your account and join the Distributed computing team Russia (click "Join").
Portal "Eternal youth" www.vechnayamolodost.ru13.05.2009