Help Cure Muscular Dystrophy, Phase 2, Помоги вылечить мускульную дистрофию, 2 фаза Налаштування

[Rilian]

Помоги вылечить мускульную дистрофию, 2 фаза / Help Cure Muscular Dystrophy, Phase 2

Как присоединиться читайте в главном топике World Community Grid

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• обзор проекта на английском
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• Статистика % выполнения 2 фазы проекта в виде графика
• Официальный форум

Введение
В 1986 году был идентифицирован первый ген (dystrophin gene), вовлеченный в дистрофию Дюшена, самую общую форму мышечной дистрофии. Благодаря генетическим исследованиям сегодня известно более 200 генов, вызывающих нервно-мышечные болезни. Однако, до сих пор знания о функциях и взаимодействии между собой белков, закодированных этими генами, остаются крайне незначительными. Раскрытие механизмов возникновения и развития нервно-мышечных заболеваний (патогенез), учитывая большое количество вовлеченных в него генов и кодируемых ими белков, становится все более сложной задачей по мере увеличения наших знаний в этой области.

Все клетки содержат одинаковую генетическую информацию в виде ДНК, которая в целом образует геном организма. Процесс экспрессии генов (у человека найдено более 20 тысяч генов), содержащихся в геноме, приводит к образованию белков (более 45 тысяч, т.е. в среднем один ген кодирует 1,6 белков), без которых невозможно функционирование клеток, в том числе специфических, например, мышечных. Некоторые их этих белков являются ферментами, другие - сигнальными молекулами, а могут быть и рецепторами, специфически связывающиеся с другими молекулами (лигандами); а также - структурными белками. Конформация (геометрическая форма, которую принимает органическая молекула) белка в пространстве (3D-структура) определяет его природные функции.

Функционирование мышц зависит от многих белков. Эти белки локализованы и работают на различных уровнях - в оболочке клетки, ее протопласте (внутреннем содержимом) или в аксоне двигательного нерва, который соединяет нерв с мышечной тканью и передает команды нервной системы.

Большинство нервно-мышечных болезней возникает под действием генетических изменений (мутации в определенных генах вызывают изменения в трехмерной структуре кодируемого ими белка), приводящих к утрате белками полностью или частично их первоначальных функций или к прекращению синтезирования белка как такового. Нервно-мышечные заболевания можно классифицировать по белкам или участкам белков, видоизменившихся под действием мутации генов.

Поэтому, чтобы разобраться в природе того или иного нервно-мышечного заболевания, исследователи стремятся связать их с нарушением функциональности определенных белков. Необходимо более точное понимание взаимодействий и функций белков, вовлеченных в патогенез той или иной мышечной дистрофии.

Невозможно переоценить значимость данной информации в разработке терапевтических процедур и инновационных методов лечения большого количества нервно-мышечных заболеваний.

Цель проекта
В Help Cure Muscular Dystrophy прибегают к помощи World Community Grid в определении белок-белковых взаимодействий более 2 200 безызбыточных белков с известной структурой, информация о которых содержится в Белковом Банке данных (www.rcsb.org/pdb). Исследоваться будут также белки, которые синтезируются в результате экспрессии мутировавших генов.

Целью проекта является создание новой базы данных с информацией о функционально взаимодействующих белках. Дальнейшие исследования будут связаны с изучением участков белков, вовлеченных во взаимодействия лигандов (например, лекарств) с ДНК. Эта тема представляет значительный медицинский интерес, хотя сейчас упор делается на проектировании малых молекул (лигандов), которые нарушают (ингибируют) или улучшают работу определенных белков, намного сложнее определить, как та же самая малая молекула может прямо или косвенно влиять на другие взаимодействия белков.

Исследовательский подход
В этом проекте используется подход, в котором скомбинирована информация об эволюции (как развитие изменило белки и определило их функции) и молекулярное моделирование (вычислительное определение относительного положения двух взаимодействующих белковых партнеров), чтобы идентифицировать потенциальные взаимодействия.

Молекулярное моделирование объединяет теоретические методы и вычислительные способы для моделирования поведения биологических молекул. Эти методы и способы применяются для исследования структуры биологических систем, таких как свернувшиеся белки, или при идентификации белков-лигандов, связывающихся с небольшими химическими системами, крупными биомолекулами и белковыми комплексами.

Докинг (стыковка) белок-лиганд - молекулярная техника моделирования, которая прогнозирует положение и ориентацию (трехмерную структуру) белка относительно лиганда (который может быть другим белком, ДНК или лекарственным средством). Методы молекулярного докинга основаны исключительно на физических принципах — даже белки с неизвестными или слабо изученными функциями могут быть исследованы на предмет стыковки с различными лигандами. Единственным обязательным условием является знание трехмерной структуры белков, полученное теоретическими методами или в ходе экспериментального исследования.

При использовании молекулярного докинга производится перебор известных молекул из баз данных с целью поиска вариантов, обнаруживающих сродство, т.е. хорошо связывающихся друг с другом. Степень сродства определяется с помощью оценочной функции по геометрическим и химическим параметрам полученного соединения. Геометрия оценивается по тому, насколько хорошо сочетаются трехмерные структуры белка и лиганда (должны быть подогнаны как рука под перчатку). С химической точки зрения оценивается сила межатомных взаимодействий между белком и лигандом.

Для таких сложных структур как белки (наименьшие из которых содержат сотни атомов) исследования белок-белковых взаимодействий могут потребовать значительных вычислительных ресурсов. Без World Community Grid вычисления, необходимые для моделирования молекулярного докинга, были бы слишком трудоёмкими. Для первых 168 белков, изучавшихся еще в первой фазе проекта, привлеченное с помощью WCG процессорное время составило 8 000 лет. Во второй фазе проекта, где будут исследоваться уже 2 246 белков, предполагаемое время расчетов достигнет 91 680 лет.

Преодолеть этот вычислительный барьер поможет информация об эволюции белков, позволяющая предсказывать взаимодействующие участки белков. Этот предварительный анализ уменьшает предполагаемое время вычислений в 100 раз, тем самым увеличивая количество исследуемых белков. Тем не менее, без помощи World Community Grid запланированные вычисления окажутся невыполнимыми.

Добровольцы, жертвующие свободные вычислительные ресурсы World Community Grid, высвободят мощности для других исследований, проводимых AFM, CNRS, INSERM и пр. научными игроками, направленных на развитие научных инструментов, которые увеличивают наши знания о природе и методах лечения редких заболеваний.

Исследователи
Вычислительная биология:
* Dr. Alessandra Carbone, Analytical Genomics, FRE3214 CNRS-UPMC, Universitй Pierre et Marie Curie, Paris.
* Yann Ponty, Department of Computer Science, Universitй Pierre et Marie Curie, Paris.

ГРИД-технологии:
* Jean-Marie Chesneaux team, Computer Science Laboratory of Paris 6 (LIP6), CNRS Laboratory UMR 7606, Universitй Pierre et Marie Curie, Paris.

Миопатия (заболевание мышц):
* Pascale Guicheney team, INSERM Laboratory U582, Myology Institut, "Pitiй-Salpetriиre" Hospital, Paris.

Молекулярное моделирование:
* Richard Lavery, Institut de Biologie et Chimie des Protйines, CNRS UMR 5086, Universitй de Lyon.
* Sophie Sacquin-Mora, Laboratory of theoretical biochemistry, CNRS Laboratory UPR9080, "Institut de Biologie Physico-Chimique", Paris.

Вопросы и ответы по проекту:

(Show/Hide)

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:

* 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.

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.

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) http://protsci.highwire.org/cgi/content/abstract/12/6/1271

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?

UPMC stands for University Pierre et Marie Curie (http://www.upmc.fr). For more information about how UPMC is involved in this project, please click here.

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, Universitй 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

Скриншот графического клиента

График производительности проекта:




Це повідомлення відредагував Rilian: Dec 11 2010, 14:10

[Rilian]

Стат на офсайте уже год не обновлялся

[Death]

хотел сказать "ну да это же вцг", но потом передумал

[re_SET]

Пишут что досчитается через 11 дней

Задания еще есть!
Вопреки побаиваниям успеваю накранчить два года в проекте ))

[Bel]

"I know our prior estimates for the completion date indicated that we would be done already. However, those estimates did not factor in delays required to handle the children and grand-children work units. Our new estimate is that we will complete this project in a little more than 5 weeks from now. We expect the researcher to provide an update soon after that. Thanks go to everyone who has contributed to this project."

[Rilian]

Here are some (hopefully accurate) information summarizing some scientist posts sent during the last 3 years.

Because of the computation complexity, the screening has be planned to be performed in several steps.

HCMD1 served to realize a first screening for identifying candidates for more detailed investigation and for identifying the most appropriate docking areas.
Based on HCMD1 results, HCMD2 served to investigate more deeply the identified candidates.
The current "re-work" (since Spring 2012) served to challenge some of HCMD2-results.



Maybe, many of the members are not really aware about pharmaceutical and medical research. In all cases, what we are doing at WCG is real research life:

Planning
Investigating
Challenging
Sorting (interesting/promising vs. not/less interesting/promising)
Planning the next step
Investigating
Challenging
Sorting
...


For one final pharmaceutical product, it is usually necessary to investigate recursively at least 10'000 substances. This "success rate" is also similar for agro-business products (e.g. crop protection).

Worldwide, many scientists will work a life long on problems without experiencing a concrete and full success.
In vitro and in silico (computational bio-science) researches are necessary for helping to identify "faster" the "right" product.

Pharma research and development require for a new product at least between 7 and 10 years; some products require much more.

In 2008, Raphaël Bolze wrote his PhD thesis about the HCMD project. It is a very interesting and explaining document about the work we support with HCMD.

Enjoy,
Yves

[Rilian]

THANK YOU from all the scientists of the HCMD project

Dear All,

We are at the end of HCMD2 and I would like to thank you for the patience and persistence in running our docking program on your machines. The huge amount of cross-docking data that we collected, thanks to you (!), has been realized for the first time. It is a mine of information for our research in protein-protein interactions and it will also constitute a precious amount of information for our colleagues around the world interested in molecular docking.

We finished analyzing the data on the 168 protein complexes run on HCMD1 and we now know what has to be done next. We shall integrate novel and quantitative, experimental data on protein binding to predict not only the conformation of interacting proteins, but also which proteins will interact and how strongly. This involves four specific challenges:

1) Obtain quantitative experimental data on protein interactions with a wide range of binding affinities. We will use surface plasmon resonance (SPR), followed by isothermal titration calorimetry (ITC) to fully characterize the thermodynamics of protein interactions over a wide range of affinities and physical conditions (concentration, pH, temperature, …). These methods constitute ideal tools for our purpose. They will be used to quantify interactions between a set of commercially available proteins, including known interacting partners. However, we will also characterize nominally non-functional "cross-interactions" within this set to test, for the first time, the common assumption that choosing single proteins from known binary complexes, or choosing proteins from different cellular compartments, implies the absence of interaction.

2) Use evolutionary sequence data to detect protein residues involved in interaction interfaces and pairs of interacting proteins. We will identify key residues within interaction sites and co-evolution signals between pairs of interaction sites in order to predict interacting partners and integrate this information into a refined molecular docking approach, with the aim of identifying binary interactions within a large set of proteins. This goal will include constructing an automated pipeline for co-evolution analysis of single proteins and protein pairs.

3) Formulate new protein-protein interaction potentials using experimental data, molecular simulations and existing structural data. Molecular simulations coupled with free energy calculations will be used to obtain an atomic-scale view of the dissociation of a limited number of the weak and strong protein interactions studied by microcalorimetry. We will determine the extent to which complexes have well-defined conformations and fully desolvated interfaces. This data will be used to formulate and iteratively refine new interaction potentials within a coarse-grain model, which will be sensitive to binding affinity.

4) Carry out a refined analysis of the large database of protein interactions that you generated to characterize interaction networks and binding promiscuity. During stage two of the Help Cure Muscular Dystrophy project (HCMD2), the resources of World Community Grid were used to dock all possible protein pairs within a set of 2200 proteins, potentially important for understanding and treating neurodegenerative diseases. This data will be analyzed to characterize key “hub” proteins and network structures, first, with the existing energetic and residue conservation data and then with the new methods resulting from 1-3.

The methods and interaction data derived from our studies will be freely available to the scientific community by the implementation of web servers and web databases.

We will do all this with 4 years funding from the French ministry of research that was awarded to our group this year. We shall devote this grant to the development of the new tools (in biophysics and bioinformatics) mentioned above, as well as on the analysis of the HCMD2 dataset to arrive to the best prediction possible on the human protein-protein interaction network that you generated in these last two years.

To keep you informed on the development of the project, I shall provide news on the advancements in my webpage. Pointers to the publications will be given there. If by any chance I do not post news from more than 6 months, send me a reminder!

THANK YOU again to all of you from all the scientists of the HCMD1 and HCMD2 projects.

Best regards,

Alessandra

[Rilian]

еще 25 дней работы

We have 355,685 'children' and 413,437 'grand children' workunits currently waiting to loaded and run. We also have 2 days worth of work currently loaded in that is waiting to run. We have been finishing about 40,000 workunits per day. That leaves us with about 20 days of work. Given that additional grand-children and some great grand children will be generated during the running. We would expect to see somewhere around 25 days of constant work available.

[Rilian]

We have about 17 days of work to go based on the 500,000 grandchildren and estimated 50-75k great-grandchildren.

[Death]

We have about 17 days of work to go

и мышечная дистрофия будет излечима?

[Rilian]

Там ведутся серьезные работы на эту тему. Читай выше, французы дали грант лаборатории 4 года изучать результаты полученные в этой фазе проекта

[Rilian]

Тасков осталось на 9 дней!

[Rilian]

По прогнозам осталось 5 дней до конца выдачи заданий!

http://i137.photobucket.com/albums/q210/Se...CGDashboard.png

[Rilian]

26 Sep 2012
End of the Help Cure Muscular Dystrophy - Phase 2 project

Проект почти завершен, выдаются последние задания

Summary
As a result of the generous contribution of computing power from our members, the Help Cure Muscular Dystrophy - Phase 2 project is on the verge of finishing.

World Community Grid is pleased to announce, that as a result of the generous contribution of computing power from our members, the Help Cure Muscular Dystrophy - Phase 2 project is very close to being completed.

The Help Cure Muscular Dystrophy - Phase 2 project was launched on May 12, 2009. To date, World Community Grid members have processed over 113 million results which required nearly 53,000 years of computing power. This work would have taken too many years to even be attempted, using the computing resources available to the researchers at the Université Pierre et Marie Curie and joint research facilities. Using World Community Grid, this research was completed in less than 2.5 years.

The researchers are now working on analyzing the results data to determine the more detailed protein-to-protein interactions involved with neuromuscular diseases. They expect to publish their results in public databases, along with descriptive papers.

You may read about these plans in this forum post by Dr. Alessandra Carbone, the lead researcher on the Help Cure Muscular Dystrophy - Phase 2 project.

If you contributed your computer power to the Help Cure Muscular Dystrophy - Phase 2 research project, the staff at the Université Pierre et Marie Curie in Paris wish to express their sincere gratitude to you.

Don't forget - we still need your help with the other active research projects running on World Community Grid! All of these important projects need your computer time. If you had selected to only contribute to the Help Cure Muscular Dystrophy - Phase 2 project, please go to your My Projects page to review and update your project selection.

все у кого был включен только этот проект, зайдите в профиль и выставьте еще проектов, чтобы компы не простаивали когда задания закончатся

[Rilian]

Out of Steady Work
We have finally reached the end of steady work for the project. Due to the continued generation of workunits, there will be intermittent work for sometime yet, but it will not be regularly available.

Thank you all for getting us to this point!!!!!!

http://www.worldcommunitygrid.org/forums/w...ad_thread,33916

[Rilian]

Задания закончились

еще гдето 2 недели будут высылаться повторные но если у вас включен только этот проект рекомендую проверить настройки и добавить другие проекты