[独立平台] [生命科学类] Folding@Home

vmzy

April 03, 2012
Receptor Binding by the Influenza Virus
The Kasson group has recently published an article in the journal Biochemistry on how influenza binds cell-surface receptors. In this article, we discuss how computational techniques can be used for further analysis of structural and biochemical data on glycan binding by influenza. We review prior work that we have done in collaboration with the Pande group, including research using Folding@home. Those earlier papers can be found here and here.


The table-of-contents graphic from our recent paper shows how dynamics the glycan (sugar) residues on the surface of the influenza hemagglutinin protein can be. 20 structures of the glycan molecules are superimposed on the receptor-binding pocket of hemagglutinin.
大意：
Kasson小组在生物化学杂志上发表了，有关流感病毒如何与细胞表面受体结合的文章。文章阐述了计算技术（FAH）在研究中起到的作用。

vmzy

April 05, 2012
Support for new GPUs (such as Kepler) in the v7 FAH client



In the past, support for specific GPUs was built into the client.  We are working on ways to automatically update this information more easily within the v7 client to support new GPUs, such as the Kepler GPUs which have just came out.  While the automatic update isn't ready yet, here is how one can manually do this:

1) Download the GPUs.txt file from https://fah-web.stanford.edu/file-releases/public/GPUs.txt

2) Copy the downloaded GPUs.txt file to the client's run directory.  The run directory is also called the data directory.  It's the same location as the 'client.db' file.  In Windows there is a link to this directory in the start menu.

3) After installing the file you must restart your client.

The client has a built-in GPUs.txt which it will use if it does not find one on disk.  The client will print a message to the log, very early on, when it reads GPUs.txt from the run directory.

In a future version of the v7 client, this will happen automatically, but for now, we are updating this file on our web site and donors can do this update manually for new hardware.
大意：
v7新增对Kepler显卡的支持，不过由于v7的自动更新功能还未实现，所以你需要手工下载GPUs.txt并放入FAH的数据文件夹中（开始菜单-FahClient-Data Directory），然后重启客户端即可生效。

vmzy

April 09, 2012
Understanding the folding of hIAPP, the peptide linked to the Type 2 diabetes

Here's an update from Prof. Xuhui Huang's lab at Hong Kong University of Science and Technology, another collaborating labortory in the Folding@home consortium.
In addition to the molecular recognition processes, another project his lab is working on at the Folding@home platform is to explore the folding free energy landscape of the human islet amyloid polypeptide (hIAPP). hIAPP (also called amylin) is a 37-residue peptide and its aggregation reduces working β-cells in patients with Type 2 diabetes. As an intrinsically disordered protein, hIAPP monomer does not have a folded global minimum in its folding free energy landscape, but contains many stable local minimums. Thus understanding the nature of these locally metastable states can help us to understand the mechanisms of the hIAPP aggregation, and further design small molecules to inhibit the amyloid formation.
Just as we have seen in the Pande lab simulations of the Aß peptide in Alzheimer's run on Folding@home previously, this research may offer potential therapeutic agents for Type 2 diabetes. At Folding@home, we are currently running extensive molecular dynamics (MD) simulations and construct Markov State Model to elucidate the free energy landscape of the hIAPP monomer. Projects 2974 and 2975 are related to the above project. We would like to thank all the Folding@home donors for your help to make our research possible.
大意：
香港的黄教授，还有个研究项目是，研究淀粉不溶素聚合体在抑制淀粉合成方面的作用，以寻找治疗2型糖尿病的方法。对应的任务编号是2974和2975。感谢大家的贡献。

vmzy

April 15, 2012
Introducing the Voelz lab at Temple, a new member of the FAH Consortium

GUEST POST: Prof. Vincent Voelz, Temple University
The Voelz Lab just started this past August in the Department of Chemistry at Temple University in Philadelphia, PA. We have just installed two Folding@home servers, and are gearing up to run simulations this summer (which I hope to talk about in future blog posts). In the meantime we have been very lucky to work with the Institute for Computational Molecular Science here at Temple, and a new high-peformance computing cluster to generate some initial data.
One of our interests is using molecular simulation to do computational design of folding and binding properties. Design efforts require looking at folding for lots of different possible protein sequences, which is a natural task for a distributed computing platform like Folding@home. We're working on ways to leverage Markov State Models of conformational dynamics to do efficient estimation of the effects of sequence perturbations. A good starting point to test these ideas are to look at proteins for which many sequences have been characterized, to see if we can predict sequence-dependent changes. Many of these sequence mutations are important in human diseases, so we hope to gain insight into these process as well.

大意：
费城的Voelz教授，安装了2台FAH服务器，加盟FAH。

vmzy

April 22, 2012
Peptoids

GUEST POST: Prof. Vincent Voelz, Temple University
One of the projects we're excited about in the Voelz Lab is molecular simulation of synthetic polymers called peptoids. These are biomimetic molecules that can fold like proteins, but they have different structural properties. Several peptoids have been identified that can fold into unique three-dimensional structures, but better computational modeling is needed to identify the driving forces for folding and predict stable peptoid structures. If we can develop tools to do this, peptoids have the potential to be an amazing platform to design functionalized nanostructures that can be used for all kinds of applications, from biotherapeutics to nanomaterials.
So far, we have shown that modern forcefields can accurately fold peptoids (DOI: http://dx.doi.org/10.1002/bip.21575) and are working with experimental collaborators on blind predictions of peptoid structure (stay tuned for more results here soon). This summer, we hope to be using Folding@home to commence large-scale simulations of peptoid folding for many peptoid sequences, in order to better understand peptoid folding mechanisms and design principles. We look forward to working closely with Folding@Home donors and testers on moving these projects forward -- you will no doubt see us on the forums frequently!

One of the projects we're excited about in the <a href="http://voelzlab.org/">Voelz Lab</a> is molecular simulation of synthetic polymers called <a href="http://en.wikipedia.org/wiki/Peptoid">peptoids</a>. These are biomimetic molecules that can fold like proteins, but they have different structural properties. Several peptoids have been identified that can fold into unique three-dimensional structures, but better computational modeling is needed to identify the driving forces for

大意:
我们研究的另一个热点是模拟高分子聚合物——类胨。它可以像蛋白质一样折叠，不过有着不同的结构特性。有些类胨甚至可以折叠出独特的三维结构。类胨的应用前景非常广泛，从生物治疗药物到纳米材料。

经过一系列的先期研究和优化，我们计划于今夏开始大规模的类胨折叠研究。以更好的了解类胨的折叠机制和设计原则。

vmzy

April 26, 2012
FAH logo mosaic
We wanted to find a way to express in a single picture the immense collective effort that FAH donors and FAH teams comprise. We had several ideas internally and this is one of my favorite: we made a photo mosaic of the FAHicon out of team logos. We also have a link to a high res version.

大意：
官方合作伙伴徽标马赛克。

vmzy

May 28, 2012
Folding@home Consortium Conference 2012
On Friday May 25 at Stanford University, we had the first "all-hands on deck" scientific conference for the Folding@home Consortium. The goals were to discuss recent scientific advances, share new techniques for how to better use FAH, as well as to plan for new infrastructure advancements in FAH for the next year.
I'll blog about some important news from the meeting in future posts. For now, I'll mention that the meeting worked out very well, with lots of new scientific advancements mentioned as well as great discussions on how we can make FAH better from the scientific and donor points of view.
Here's a picture of (almost all of) the attendees.

Pictured, from top left, going right: TJ Lane (Stanford), Dr. Jason Wagoner (Stanford), Prof. Dr. Vincent Voelz (Temple), Dr. Sidney Elmer (Sandia National Lab), Dr. Fancesco Pontaggia (Brandeis), Dr. Lan Hua (UCSF), Bruce Borden (FoldingForum.org), Joseph Coffland (Cauldron Development), Dr. Diwakar Shukla (Stanford), Dr. Lee-Ping Wang (Stanford), Steven Kearnes (Stanford), Kyle Beauchamp (Stanford), Dr. Greg Bowman (UC Berkeley), Dr. Relly Brandman (UCSF), Robert McGibbon (Stanford), Prof. Dr. Yu-Shan Lin (Tuffs), Prof. Dr. Matt Jacobson (UCSF), Prof. Dr. Jesus Izaguirre (Notre Dame), Prof. Dr. Vijay Pande (Stanford), Prof. Dr. Michael Shirts (University of Virginia), Dr. John Chodera (UC Berkeley/QB3), Prof. Dr. Peter Kasson (University of Virginia), Prof. Dr. Xuhu Huang (Hong Kong). Not shown: Prof. Dr. Chris Snow.
大意：
2012FAH代表大会于5月25日顺利召开，讨论了当前取得的进展及未来的发展思路。相关详细信息今后会陆续更新，敬请期待。

vmzy

May 29, 2012
FAHcon 2012: Dr. Greg Bowman

Here's a guest post from Dr. Greg Bowman about FAHcon 2012.

I had the opportunity to present two projects at the first Folding@home conference (which was a terrific event!).  The first project focused on new protein therapeutics.  It has long been known that a protein called IL-2 can help stimulate an immune response, so in theory giving people with diseases like immune deficiencies IL-2 could be tremendously helpful.  In practice, however, giving them IL-2 often leads to severe heart problems.  To find a better solution, collaborators at Stanford designed a variant of IL-2 that can stimulate an immune response without causing any side effects.  However, they couldn't understand how it worked because the two proteins had almost identical structures!  Using Folding@home, we showed that IL-2 is a relatively floppy protein while our collaborators' variant is locked into a structure that is poised to stimulate an immune response.  The second project highlighted some new methods I've developed that could allow us to predict such behavior so that next time we can go recruit experimentalists instead of waiting for them to bring us interesting problems.
大意：
2012 FAH代表大会委员：Dr. Greg Bowman
‘提案’简介：
1、IL-2变异蛋白研究。IL-2可用于刺激免疫系统，增强免疫力，但是对心脏有副作用，斯坦福合作者开发了IL-2变异蛋白，不仅保持了药效却完全没有副作用。不过具体机理却搞不清楚，为啥结构几乎一致的蛋白质有此不同的功效。经过FAH的模拟研究，发现原始IL-2蛋白结构比较松散，而IL-2变异蛋白却比较稳定，使它只能对特定免疫系统起作用（减少过敏症状）。
2、研究新方法，可以在测试前预测药物的功效，而不是傻等测试结果，有问题可以提前发现，加快新药物研发速度。

译者注：FAH代表大会期间，会有大量‘委员提案’公布，大家请慢慢看，对官方的工作有个了解。
这个代表大会可比我朝party大会靠谱多了。某些阴谋论者您还是多怀疑下俺们的party吧。

vmzy

May 30, 2012
FAHcon 2012: Prof. Dr. Peter Kasson

Here's a guest post from Prof. Dr. Peter Kasson (University of Virginia).

FahCon2012 was quite an exciting conference.  We shared some of our work relating both to new methodology and to our mixed computational & experimental work on influenza.  We also enjoyed hearing about many important developments from other FAH researchers.

Why do we study influenza?  First, influenza kills about 40,000 people each year in the US alone and many more worldwide.  These are mostly children under 2 and adults over 60, but all of us who hope to live past 60 and have children we care about find this a matter of some concern.  Second, influenza has a proven track record of causing global mass-mortality events, such as 1918.  A similar virus today might easily kill in the range of 60 million people, and we’d like to be prepared.  Third, influenza is an important model system for understanding other viruses such as HIV and cancer-causing viruses such as HPV, Heptatitis C virus, and Epstein-Barr virus.  It may come as a surprise, but many cancers are virus-associated, and these form an important area for prevention.

We have done a lot of work on how influenza gets into cells to replicate in the first place.  This is an important therapeutic target, and it’s also critical for understanding why viruses like H5N1 “bird flu” have not become efficiently transmissible between people.  Some of our new work looks at the protein folding in the membrane required for viral entry.  We have some exciting new results that we’ll blog about as soon as they’re published.

We also presented new developments on a software package that we’re very excited about:  Copernicus.  The Kasson, Lindahl, and Pande groups published a paper on Copernicus at SC11 last year, and the Kasson and Lindahl groups have been continuing development extensively.  Copernicus essentially makes the back-end control of large-scale simulations much more transparent, so FAH researchers will be more easily able to integrate new methods.  It also runs on supercomputers and cloud-computing platforms, so we can use these in addition to FAH, and non-FAH researchers can perform the same style of computation that we do on FAH.  Since these changes are all on the server side, FAH donors shouldn’t notice a difference, but we’re excited about the new science that Copernicus can enable.  
大意：
2012 FAH代表大会委员：Prof. Dr. Peter Kasson (University of Virginia)
‘提案’简介：
我们主要研究的是流感。
首先，在米国，每年大约有4万人死于流感（其他国家更多），其中大部分为2岁以下儿童和60岁以上老人。
其次，历史上流感曾造成大量人口死亡事件（例如1918年大流感）。现今如果流感一旦卷土重来，很可能造成6千万人口的死亡，我们必须防患于未然。
最后，流感是研究、预防病毒的好模型，比如HIV（艾滋），引起癌症的HPV、Heptatitis C、Epstein-Barr病毒（不要觉得惊奇，大部分癌症都与病毒有关）。

我们已经对流感如何入侵细胞、如何复制做了大量研究，这对药物研发有大作用，而且也解释了，为啥禽流感（如H5N1）不会在人类中大规模传染。现在我们在研究，与病毒入侵有关的细胞膜蛋白质折叠，现已取得一定进展，一旦结果发表，我们会及时发消息通知大家。

去年我们还开发了Copernicus软件包，它是一个全新的计算框架，可以方便的整合新算法，并且可以在超级计算机和云计算平台上使用，进行大规模模拟。

vmzy

May 31, 2012
FAHcon 2012: Prof. Dr. Michael Shirts

Here's a guest post from Prof. Dr. Michael Shirts (University of Virginia).

The open source Gromacs molecular simulation engine has been one of the main simulation tools in Folding@Home for almost a decade.  I discussed new tools being introduced in Gromacs 4.6 that will be very useful for biomolecular studies run on Folding@Home.  In particular, these new tools will make it much easier to quantitatively estimation the interaction strength of small molecules with proteins.  Knowing the strength of these interactions makes it possible to predict how effective proposed new drugs will be.
大意：
2012 FAH代表大会委员：Prof. Dr. Michael Shirts (University of Virginia)
委员简介：
FAH使用Gromacs作为计算内核已经有10年了。如今准备整合4.6版的新功能。新版能更好的评估小分子和蛋白质的相互作用力，这能更有效的预测新药的药效。

vmzy

June 04, 2012
FAHcon 2012: Prof. Dr. Chris Snow

Dr. Snow, a new investigator at Colorado State University, gave a presentation focused on upcoming research. A unifying theme of this research is the engineering of new, synthetic proteins with applications in bioenergy & medicine. Specifically, Snow and colleagues are using computational protein design to engineer new cellulase enzymes for more efficient and economical biofuel production. To facilitate these calculations, the Snow group is developing software (SHARPEN) that could be deployed on the Folding@Home network. The technical barriers to developing a SHARPEN F@h core were discussed. Notably, F@h can still contribute to these design problems using existing molecular dynamics simulations.
大意：
2012 FAH代表大会委员：Prof. Dr. Chris Snow (Colorado State University)
委员简介：
主要致力于生物质能和医学研究。当前正在研究木纤维质酵素，以更加有效、经济的进行生物燃料生产。他们开发了SHARPEN软件用于相关计算。目前我们正在讨论是否将其移植到FAH上。

vmzy

June 06, 2012
FAHcon 2012: Prof. Dr. Xuhui Huang

Here's a guest post from Prof. Dr. Xuhui Huang, from the Hong Kong University of Science and Technology.

I had a great time attending the first annual FAH conference and enjoyed the nice summer weather in the Bay area.  We had plenty of discussions on the recent progress and future plans of FAH on both scientific and technique sides.  I look forward to the future FAH conferences.

In my talk, I reported recent results on two projects from our lab.  The first one is the development of a new algorithm for the automatic construction of Markov State Model to investigate the conformational dynamics of multi-body systems.  This new algorithm holds great potential to help elucidate the aggregation mechanisms of multiple misfolded peptides to form oligomers and eventually fibrils.   In the future, we plan to apply this algorithm to study the human islet amyloid polypeptide (hIAPP) peptides, and its aggregation may result in reducing working β-cells in the Type 2 diabetes patients.

I have also presented our recent results on applying Markov State Models to elucidate the molecular mechanisms of gene transcription.  Transcription is the first step in reading genomic DNA.  Transcriptional regulation plays a key role in cell differentiation and other fundamental processes. Misregulation of transcription is a major factor in cancer and other human diseases.  Thus, elucidating the mechanism of transcription is crucial for understanding these processes.  Our simulation results are able to provide dynamic information for the transcription, and this dynamic information is largely inaccessible to present experimental techniques.
大意：
2012 FAH代表大会委员：Prof. Dr. Xuhui Huang (香港科技大学)
委员简介：
当前我们在开发一种新算法，以研究多体系统构型动力学中的马尔可夫状态模型的自构，这将帮助我们解释低聚体、小纤维的多误折氨基酸的聚合机制。将来我们将用它研究胰岛素，以治疗II型糖尿病。
同时我们发表了利用马尔可夫状态模型研究基因转录的分子机制的最新研究结果。转录紊乱是导致癌症及其他疾病的主要原因。模拟结果对研究转录机制非常有用，而当前通过实验得到这些结果是很难的。

vmzy

June 08, 2012
FAHcon 2012: Thinking about how far FAH has come

To start off FAHcon2012, I gave a talk which included a review of how far Folding@home has come in the last decade.  I showed a slide from the very first talk I gave about Folding@home results.  That talk was given at Columbia University in August of 2000, and I talked about results from our paper in Science entitled "Screen savers of the world, unite!".  That work described the folding of a very small protein (16 amino acids) on a very short timescale (10ns = 10 x 10^-9 seconds!), but still was a major accomplishment for the time.

It's exciting to see how far we've come.  One way to think about it is in terms of how long of a time scale and length scale we can simulate for protein folding and protein misfolding diseases (such as Aß aggregation in Alzheimer's Disease):

Time scales: advancing roughly 1000x every 5 years

2000: 1 to 10ns  (Fs peptide)

2005: 1 to 10µs  (villin, Aß aggregation of 4 chains)

2010: 1 to 10ms  (NTL9, Lambda repressor)

2015: 1 to 10s?

Just breaking past a microsecond was a big deal.  The fact that we can simulate 10's of milliseconds is very exciting, but I'm really excited about where this appears to be leading, allowing us to tackle really challenging and important problems.  It would also mean that through a combination of new methods, algorithms, and hardware advances, we've already increased our capabilities by a million fold in just 10 years (2000 to 2010).  We're looking forward to hopefully making it a billion fold in 2015!

Length scales: advancing roughly 2x every 5 years

2000: 16 amino acids (Fs)

2005:  35 amino acids (villin)

2010:  80 amino acids (lambda, ACBP)

2015:  160 amino acids?

It's also important to note that these are sizes for protein folding.  For other problems, such as protein conformational change, we've already tackled much bigger systems.

I'm really excited to see what the next 5 years will bring!
大意：
2012 FAH代表大会：FAH进展总结
随着算法的改进、志愿者的增加及硬件的升级，FAH取得了巨大的发展。
就模拟时间而言每5年提升1000倍。
2000: 1 to 10ns  (Fs peptide)
2005: 1 to 10µs  (villin, Aß aggregation of 4 chains)
2010: 1 to 10ms  (NTL9, Lambda repressor)
2015: 1 to 10s?
模拟复杂度每5年提升2倍
2000: 16 amino acids (Fs)
2005:  35 amino acids (villin)
2010:  80 amino acids (lambda, ACBP)
2015:  160 amino acids?

vmzy

June 25, 2012
Protein Folding Conference
Guest post: Dr. Greg Bowman, UC Berkeley
We just had a protein folding conference at Stony Brook University in New York that was extremely encouraging. Both the experimental and theoretical communities are very excited about the results we are generating with Folding@home. In particular, they are excited about (i) our increasing ability to make quantitative connections with experiments and (ii) the long timescale dynamics for large proteins we are now able to capture. For example, we recently succeeded in folding an 80-residue protein on 10 millisecond timescales (paper is here). For reference, that’s about twice as many residues and about 1,000 times longer timescales than what most anybody else is able to achieve! There are now multiple experimental groups who are asking us to make predictions for them to test. So, we appreciate all your help and have plenty of new calculations for you to contribute to.
大意：
蛋白质折叠大会
展示了近期研究成果。大家特别感兴趣的是：1、我们将大量的模拟结果与实验联系了起来。2、我们的模拟时间很长。例如，最近我们成功的对80个残余的蛋白质进行了10毫秒的模拟。它的残余数量是其他最好结果的2倍，时间是1千倍。很多实验室表示愿意与fah合作，进行蛋白质预测研究。

vmzy

July 02, 2012
Guest post from Dr. John Chodera, UC Berkeley

Working toward better cancer therapies with Folding@Home

Kinases [http://en.wikipedia.org/wiki/Kinase] are the molecular logic gates of the cell.  These important proteins integrate critical signaling information in every cell of our bodies, becoming active only when specific upstream signals are received.  However, in many kinds of cancer, mutations can emerge in one or more kinases that cause them to ignore these regulatory signals and become active all the time.  If these kinases are involved in cell division, this can erroneously cause cells to keep dividing even when they shouldn't, potentially resulting in a form of cancer.  

Our group [http://choderalab.org] is using Folding@Home to understand how some successful anti-cancer therapeutics (like imatinib [http://en.wikipedia.org/wiki/Imatinib]) are able to selectively target the targeted disease-causing kinases while minimally interfering with other normally-functioning kinases.  A deeper understanding of this selectivity would help recapitulate the success seen in treating some cancers by aiding the design of novel therapeutics targeting other cancers.  Up to now, the origin of this selectivity has been elusive because it appears that highly selective drugs like imatinib can bind in essentially the same way to the highly similar Abl and Src kinases, despite the fact that it binds Abl well and Src poorly (see Figure).  It is now believed these differences in binding are due to conformational preferences of the kinase for different geometries, something that had been traditionally hard to study but is well-suited to techniques we originally developed to study protein folding problems on Folding@Home.  

Stay tuned for future updates on how Folding@Home is helping our study of kinase inhibitors and cancer!

大意：
用FAH寻求更好的癌症疗法
激酶发生变异后会失控，使细胞一直分裂，导致癌化。
我们小组，使用fah研究，一些抗癌疗法（如：伊马替尼）为何能够只对特定的激酶起作用。籍此我们可以开发更佳的抗癌药物。