[独立平台] [生命科学类] Folding@Home

vmzy

New initiative: FAH on Android
January 12, 2015 by Vijay Pande ·
I’m excited to announce today our new initiative for Folding@home on Android Mobile phones, with a beta version being released today.  In collaboration with Sony, we have brought Folding@home to Sony Mobile phones starting today with broader Android support in the coming months.  The rationale for moving FAH to mobile phones is simple: there are millions of phones and they are becoming extremely powerful.  Indeed, with our open source OpenMM code (http://openmm.org) optimized for mobile phones, we get performance comparable to what we were getting on desktops just a few years ago.  Moreover, we have completely rewritten our server backend in order to handle the needs of mobile devices.  In particular, our Streaming Backend (also known by its internal project name ‘ocore’) can seamlessly distribute work from one phone to another, so even a short amount of compute time on a phone can make an immediate contribution to our project.

With the computer power available, we plan on tackling two key challenges.  First out the door is a project on breast cancer.  In this project, we are investigating the nature of drug resistance mutations in key proteins (kinases) that are targets for breast cancer drugs.  By studying the nature of how these mutations change these key drug targets, we will be able to both advance our basic biophysical understanding of these key proteins as well as build a tool to be used for patient specific breast cancer treatment –– by sequencing the tumor and seeing what mutations are present, our tool seeks to recommend the best drug for a specific patient.   Next, we plan to follow this project with a protein folding project, related to misfolding disease (eg Alzheimer’s Disease).

Note that this is a first beta release and certain elements are not in place just yet.  Nevertheless, we’re very excited about this next step forward, both that we’re moving into a new space but also that we’ve put the pieces in place such that mobile can make a significant contribution.  We have other projects going on as well, so look for other announcements in 2015 for additional FAH initiatives.
大意：
FAH首发安卓测试版客户端
在sony的协助下，我们开发了FAH安卓版客户端。迁移到手机的原因是，因为手机的性能和数量越来越大。我们已经针对手机优化了OpenMM代码。同时把服务器端代码进行了升级（内部代号ocore），可以利用手机的碎片化时间进行无缝计算。
手机上我们将推出两个项目。首先是乳腺癌项目，研究乳腺癌细胞的抗药性。第二个项目是有关阿兹海默的。

vmzy

Src kinase: Project 10471
January 26, 2015 by Sonya Hanson ·
In Project 10471 we at the Chodera lab are looking at Src kinase. The Src gene was first discovered as responsible for the tumorogenicity of Rous sarcoma virus. This gene is also present in animals, and it is in fact a mutated Src gene that is injected back into the host that causes cancer, not a viral gene. The discovery that cancer was a result of mutated naturally occuring genes and not viral ones was a milestone in cancer research and Harold E. Varmus and J. Michael Bishop were awarded the Nobel Prize in Physiology or Medicine for this and related discoveries of the cellular origin of retroviral oncogenes in 1989.

Since then Src has been found to be over-expressed and/or highly activated in a variety of cancers, most notably linked to metastasis in breast, prostate, and colon cancers. The drug dasatinib of Bristol-Myers Squibb (Sprycel commercially), has been approved for treatment of CML (described more fully in our blog post on Abl kinase), but it was also recently in clinical trials for metastatic prostate cancer due to its affinity for Src kinase.

We are not only interested in Src kinase for its intrinsic value, but also to compare and contrast its behavior with Abl kinase in Project 10472. While dasatinib targets both Src and Abl kinase, only Abl and not Src is sensitive to the drug imatinib, despite the nearly identical imatinib bound poses seen in the Src and Abl crystal structures (pictured). Because these static structures are so similar, we are looking forward to using the long timescale simulations of these two kinases on Folding@home to help us understand their different small molecule binding properties.

大意：
10471项目主要研究Src激酶，在很多癌症（如：乳腺癌，前列腺癌，直肠癌）中Src激酶都会出现过度表达。现有药物达沙替尼对Src激酶有效。
10472项目主要研究Abl激酶。虽然达沙替尼和伊马替尼的靶点都是一样的，但是伊马替尼只对Abl激酶有效，对Src激酶无效。对此我们将对两种激酶进行横向对比，以期发现其中的奥秘所在。


Cancer Systems Biology Scholars Program
January 28, 2015 by Vijay Pande ·

I’m happy to announce our participation in the Cancer Systems Biology Scholars (CSBS) program, which provides a unique opportunity for postdoctoral training in cancer systems biology in a dynamic, multi-disciplinary environment.  A diverse group of mentors, all with independently funded research projects in cancer research, participate with expertise in many disciplines. CSBS trainees will conduct research, participate in specialized coursework and seminars, and attend a regular meeting of CSBS mentors and trainees, as part of an integrated, two-year program.

For those looking to be a postdoctoral fellow in the program, I encourage you to apply:

http://med.stanford.edu/csbs/apply/

This would be an opportunity to work on Cancer in the Pande Lab/Folding@home or with any of the other mentors associated with the CSBS at Stanford.  The application deadline is March 2, 2015. Priority will be given to applications received by March 2. Applications received after March 2 will be considered until positions are filled.
大意：
Pande实验室加入了癌症系统生物学者培养计划，博士后可以申请加入。


Big Adv Program Ends January 31
January 31, 2015 by Vijay Pande ·
As we have previously announced, the bigadv (BA) program will reach end-of-life on January 31, 2015.  We would like to thank all the donors who have contributed to the program.  Throughout the history of Folding@home, donor participation has enabled us to tackle hard problems and engage in bold experiments.  The BA program is an example of both of these––the projects in BA are one that simply could not have been addressed otherwise.  We are still analyzing the results of these projects, but the preliminary data already yields some exciting results that we are comparing to experiments.

Although the BA program is ending, we recognize that the many-core systems previously used to run BA may not perform optimally on all work units in the Folding@home ecosystem (although they will do quite well on most).  In an ideal world, we would have each project performance-benchmarked on a wide variety of systems and a dynamic allocation scheme that matches clients to projects that perform well on their hardware while ensuring a distribution of client capability across Folding@home scientific priorities.  However, this sort of matching is more technically involved (and places larger demands on the assignment server) than we are able to offer at this time.  At BA end-of-life, in order to make sure that these many-core get WUs best suited for them, clients continuing to use the BA flags will be directed to large work units, although these will carry the normal Folding@Home points scheme rather than a BA scheme.  We are planning to expand the diversity of these work units to include a variety of “large” simulation problems, but at this point we are not making statements as to the anticipated longevity of this scheme.

Thank you once again for contributing to Folding@home, whether the BA program or any of our other initiatives.  All our past and future scientific achievements are due to your participation and generosity.
大意：
BA项目将于1月31日结束。BA的结果还在分析中，早期的数据生成了令人振奋的结果，我们还在和实验室数据进行比对。
虽然BA项目结束了，但是我们发现参与BA的‘类超级计算机’如果直接算普通的SMP任务，会对现有的积分系统和任务服务器，产生一定影响。所以对于加了BigAdv标签的用户，我们将放出定制的大包。不过将采用普通任务的奖励标准。

Huntington’s Disease Society of America SF Celebration of Hope
January 29, 2015 by Vijay Pande ·
HD-SF-2015On Saturday May 30th, 2015, the Huntington’s Disease Society of America SF Celebration of Hope will Honor Prof. Pande for his work with Folding@home.  Details are in poster to the right (click on it to enlarge it) and this link.

大意：
2015年旧金山亨廷顿舞蹈症希望之家，为Pande教授颁奖，以感谢他和FAH在疾病研究方面做出的贡献。

vmzy

Video on the technical details of FAH
February 19, 2015 by Vijay Pande ·
Here’s a video on the more technical details of Folding@home:  how it works, what we’ve done, where we’re going, etc.  It’s a recording of a talk I presented at the NCSA at the University of Illinois in 2014.
http://www.youtube.com/embed/CkeTGaUKYrA?feature=oembed
大意：
这个是2014年我在伊利诺伊州州立大学NCSA大会上做的演讲视频，介绍了有关FAH的技术细节。

vmzy

Modeling cyclic RGD peptides
February 24, 2015 by Vincent Voelz ·
RGD peptides (those which contain a conserved Arg-Gly-Asp sequence) can adopt a hairpin loop structure found in integrin-binding proteins such as fibronectin, fibrinogen, and vitronectin. Over the last few decades, researchers have sought to develop cyclic RGD peptides that can bind potently to integrin, an important cancer target. The most successful of these to date, cilengitide (cyclo-RGDf-[N-Me]V), was discovered using a strategy of screening various chemical substitutions to find designs whose structures were more rigid. Cilengitide inhibits the binding of tumor cells to the extracellular matrix, which prevents vascularization and induces cell apoptosis. While cilengitide in particular has performed disappointingly in recent phase III clinical trials against glioblastoma, cyclic peptides in general are an exciting new platform for drug development.

In several projects soon to be released to Folding@home, we are trying to understand how to design rigid cyclic peptides in silico. First, we are have been quantifying just how accurate molecular simulations are at predicting the conformational properties of cyclic RGD peptides in solution. In a submitted manuscript, we report excellent agreement with previously published experimental data. Second, we are simulating the binding of cyclic RGD peptides to integrin to understand the relative contributions of conformational entropy (i.e. rigidity) and enthalpy (i.e. the strength of the intermolecular binding forces). Several previous studies have shown that achieving the right balance of these factors is tricky—a problem we hope our work can address.

大意：
对精氨酸-甘氨酸-天冬氨酸环肽（译注：以下简称环肽）进行建模
环肽在与整合蛋白（如：纤连蛋白、纤维蛋白原、玻连蛋白）的结合中会形成发夹环状结构。在过去的几十年里，科学家都在试图寻找能和整合蛋白（一种重要的癌症靶点）的环肽。到目前为止取得的成绩是发现了西仑吉肽，它可以阻止细胞外基质与肿瘤细胞结合，从而使癌细胞无法血管化、杀死癌细胞。但是在针对恶性胶质瘤的3期临床测试中，西仑吉肽的表现不尽人意。所以现在科学家把注意力转向了环肽。
在FAH即将公布的新项目中，我们将对环肽的刚度进行模拟研究。首先，会对溶液中模拟的环肽构型属性数据的准确性进行量化分析，不过在刚提交的手稿中，我发现模拟数据和实验室数据吻合度非常高。其次，我们将对环肽在与整合蛋白的结合进行模拟，以分析构象熵（刚度）和焓（分子间结合能）对分子结合过程的影响。

vmzy

Combining Markov state models and experiments to find new druggable sites
February 24, 2015 by Greg Bowman ·
Rational drug design efforts typically focus on identifying inhibitors that bind to protein active sites. Pockets that are not present in crystallographic structures yet can exert allosteric (i.e., long-range) control over distant active sites present an exciting alternative. However, identifying these hidden allosteric sites is extremely challenging because one usually has to simultaneously find a small molecule that binds to and stabilizes the open conformation of the pocket. In our new PNAS paper, the Bowman lab presents a means of combining advances in computer modeling—using Folding@home and Markov state models to capture long timescale dynamics—with biophysical experiments to identify hidden allosteric sites without requiring the simultaneous discovery of drug-like compounds that bind them. Using this technology, we discover multiple hidden allosteric sites in a single protein.
大意：
结合马尔可夫模型和实验室数据发现新的药物靶点
传统的药物研发都是需要蛋白质的活跃靶点，却找不到隐藏的变构靶点。如今鲍曼实验室，利用FAH的模拟数据和实验室数据，成功的找到了隐藏的变构靶点。

vmzy

Updated psummary page
February 25, 2015 by Vijay Pande ·
Our psummary, or project summary, is a Web page we publish which lists information about all currently active folding projects.  Last fall, we updated psummary to work with our new assignment server (AS).  Initially, we published the new psummary to a new URL and left the old psummary in place.

Since the old psummary does not contain information about some new projects, and the new psummary and AS have stabilized, we have decided it is finally time to deprecate the old psummary.  Next week we will replace the old psummary with the new.

This change may impact some third-party tools which parse the psummary HTML but we hope the developers of these tools will update their code soon.  To mitigate such problems in the future we now also publish the psummary data in JSON format. Third-party tools should use the JSON data instead of parsing the HTML, which may change from time to time.
大意：
去年秋天，为了对新的AS服务器代码提供支持，我们更新了项目介绍页面。当时留下了老的项目页面。如今新页面已经稳定了，所以我们决定把老页面下线。
因此，某些还在解析老页面HTML的第三方统计站点可能会出问题。为了一劳永逸的解决这个问题，我们提供了json格式的项目介绍信息。这样今后即使html页面改版，第三方也不用频繁修改解析代码。

Removal of the bonus for A4-core based projects starting March 2, 2015
February 27, 2015 by Vijay Pande ·
The A4-core bonus was a 10% bonus started in mid 2012 as a temporary bonus to incentivize Folding@home donors to upgrade their clients to version 6.34 and above, allowing scientists using FAH to be able to research larger and more complex biological problems. This has been very successful allowing us to computationally investigate much larger systems including enzymes involved in cancers and vision (see recent blog posts and published work on the Src Kinase, protein kinase C, Rhodopsin, and many others).

While the A4 bonus was designed to be temporary, it has been in place for multiple years, considerably longer than its expected lifetime of three months. We believe it is now time to retire the A4 bonus. Therefore starting March 2, 2015, A4 core based projects will no longer receive both the 10% bonus and the quick return bonus.  (They will continue to receive the quick return bonus like most other projects.)

The change should be seamless but please be aware that starting March 2, 2015, returning A4-core work units will see an approximate 10% drop in credited points.
大意：
2012年中，为了鼓励大家把客户端升级到V6.34以上版本，我们临时把A4内核的基础分上浮了10%。因为A4内核能帮科学家进行更复杂的计算。本来计划只实行3个月的，结果一眨眼3年都快过去了。因此我们决定从2015年3月2日起，停止A4任务的激励措施。

vmzy

Updated psummary page
February 25, 2015 by Vijay Pande ·
Our psummary, or project summary, is a Web page we publish which lists information about all currently active folding projects.  Last fall, we updated psummary to work with our new assignment server (AS).  Initially, we published the new psummary to a new URL and left the old psummary in place.

Since the old psummary does not contain information about some new projects, and the new psummary and AS have stabilized, we have decided it is finally time to deprecate the old psummary.  Next week we will replace the old psummary with the new.

This change may impact some third-party tools which parse the psummary HTML but we hope the developers of these tools will update their code soon.  To mitigate such problems in the future we now also publish the psummary data in JSON format. Third-party tools should use the JSON data instead of parsing the HTML, which may change from time to time.
大意：
去年秋天，为了对新的AS服务器代码提供支持，我们更新了项目介绍页面。当时留下了老的项目页面。如今新页面已经稳定了，所以我们决定把老页面下线。
因此，某些还在解析老页面HTML的第三方统计站点可能会出问题。为了一劳永逸的解决这个问题，我们提供了json格式的项目介绍信息。这样今后即使html页面改版，第三方也不用频繁修改解析代码。

Removal of the bonus for A4-core based projects starting March 2, 2015
February 27, 2015 by Vijay Pande ·
The A4-core bonus was a 10% bonus started in mid 2012 as a temporary bonus to incentivize Folding@home donors to upgrade their clients to version 6.34 and above, allowing scientists using FAH to be able to research larger and more complex biological problems. This has been very successful allowing us to computationally investigate much larger systems including enzymes involved in cancers and vision (see recent blog posts and published work on the Src Kinase, protein kinase C, Rhodopsin, and many others).

While the A4 bonus was designed to be temporary, it has been in place for multiple years, considerably longer than its expected lifetime of three months. We believe it is now time to retire the A4 bonus. Therefore starting March 2, 2015, A4 core based projects will no longer receive both the 10% bonus and the quick return bonus.  (They will continue to receive the quick return bonus like most other projects.)

The change should be seamless but please be aware that starting March 2, 2015, returning A4-core work units will see an approximate 10% drop in credited points.
大意：
2012年中，为了鼓励大家把客户端升级到V6.34以上版本，我们临时把A4内核的基础分上浮了10%。因为A4内核能帮科学家进行更复杂的计算。本来计划只实行3个月的，结果一眨眼3年都快过去了。因此我们决定从2015年3月2日起，停止A4任务的激励措施。

vmzy

Folding@Home client for Android Mobile phones
March 19, 2015 by Mark Piercy ·
We’re happy to announce that our Folding@Home client for Android Mobile phones has now entered the next stage of beta. This version is available to all Android Mobile phones with version 4.4 (Kitkat) and above. The version also contains an update of the mmlib.

Scientifically, as in our previous beta run, we continue to focus on the breast cancer with our the mobile app. In this project, we are investigating the nature of drug resistance mutations in key proteins (kinases) that are targets for breast cancer drugs. By studying the nature of how these mutations change these key drug targets, we will be able to both advance our basic biophysical understanding of these key proteins as well as build a tool to be used for patient specific breast cancer treatment— by sequencing the tumor and seeing what mutations are present, our tool seeks to recommend the best drug for a specific patient.

We are planning user experience updates in the coming months, including updates in areas suggested by donors. We have been very excited about the donor reaction so far. The beta version has been downloaded more than 150,000 times worldwide, with more than 53,000 mobile phones contributing at the same time.
大意：
FAH安卓版客户端开始进入开放公测阶段。依然研究乳腺癌关键蛋白激酶的抗药性变异。
接下来几个月，我们将着力于改进用户体验。目前beta测试版已经有15万次下载，有5.3万台手机参与。
https://play.google.com/store/apps/details?id=com.sonymobile.androidapp.gridcomputing

vmzy

NaCl client stats update
May 4, 2015 by Vijay Pande ·
Good news for NaCl donors: we’ve found an issue with one of the NaCl servers in Hong Kong that wasn’t awarding points (whereas the servers at Stanford have been), so we expect NaCl client donors to see some more points coming their way.
大意：
香港服务器发放的NaCl任务都没给分，今天补分。

vmzy

Issue with fah-web.stanford.edu
May 17, 2015 by Vijay Pande ·
Likely due to a recent extremely heavy (and unusually rare) electrical storm, we’ve had some server issues last week.  I thought we’d gotten them all but we see now that there’s an issue with fah-web.stanford.edu, which serves up both the Folding@home stats and project descriptions.  While the stats are being accumulated on a separate server, fah-web is the web server that displays them to donors.  I’ve taken a look at it and there’s a more serious issue with a particular server than I can take care of myself. I’ve filed a ticket with the sysadmin team. Best guess ETA on this being fixed is Monday at noon (assuming this is something simple).

The stats accounting is still going on and this appears to be just an issue with the web server (fah-web), so we expect that this resolution should be simple enough once our sysadmin team gets to this on Monday .
大意：
由于上周遇到罕见电涌，服务器出了问题。统计和项目介绍服务器fah-web.stanford.edu挂了。只有等周一学校IT部门的人来了才能修。实际统计数据都在另一台服务器上，没有问题，只是对外显示的服务器挂了，大家暂时看不到而已，大家不用担心。
UPDATE Monday May 18 at 10am pacific time:  We’ve got the machine back up and everything is looking good.  It appears that the problem was the server was under heavy load post storm, leading to a PERQ reset under load, a longstanding issue, which causes filesystems fo go read-only or offline, with the start of the problem was May 16 19:21:52.  We’re planning on buying new hardware to help here, especially since this hardware is on the older side now.
大意：
机器恢复正常了，貌似是由于机器负载能力不足导致文件系统锁死。我们准备升级服务器了。

vmzy

Multi-core CPU jobs
May 21, 2015 by Vijay Pande ·
We’ve been getting reports that FAH is low on CPU jobs.  We’re in the process of adding more multi-core jobs to existing projects.

Also, currently lead developer Joseph Coffland’s main project is to get a new Gromacs CPU core out to enable some new science on CPU cores (that’s currently only easily doable on GPU cores).  We expect a rough ETA for the first testing of that new core to be in a few weeks.
大意：
SMP任务告急，我们正在加新任务。
几周后我们将测试新cpu计算内核，新内核支持在cpu上算gpu任务。

译注：术业有专攻，gpu擅长的矢量计算放到cpu上，计算效率肯定酸爽吧？

vmzy

New Core tech update: OpenMM (GPU) and Gromacs (CPU)
May 29, 2015 by Vijay Pande ·
We’ve been pushing hard to improve the performance of OpenMM, especially in OpenCL as it’s now used in Folding@home.  We’ve got some great news hot off of the presses.  These are the benchmarks described at http://wiki.simtk.org/openmm/BenchmarkOpenMMDHFR.  They’re using the very latest OpenMM code, what will be in OpenMM 6.3.  They’re using CUDA 6.5 and running on Titan X.  All numbers are in ns/day.

Benchmark Calculation           CUDA          OpenCL
Implicit, 2 fs        471        366
Implicit, 5 fs        684        589
Explicit-RF, 2 fs        305        265
Explicit-RF, 5 fs        508        460
Explicit-PME, 2 fs        161        164
Explicit-PME, 5 fs        318        354


We’re especially pleased with those OpenCL PME numbers.  OpenMM Lead Developer Peter Eastman has put a lot of work into that for this release, and it now is actually faster than CUDA (For the Titan X).  Curiously, that is not the case on GTX 980.  It’s still slower than CUDA there, although it comes a lot closer than it used to.

This will be spun into an updated Folding@home core.  The upshot for GPU donors is that PPD for that new core should increase, due to the expanded capabilities of the new code.

It’s important to stress that SMP/CPU donors aren’t left out of new performance (and therefore PPD) updates either: FAH Lead Developer Joseph Coffland has been working hard on a new Gromacs core and that should also see performance benefits, as we roll out AVX support for FAH.
大意：
GPU内核进行了大幅优化，性能已经接近cuda了。
cpu内核近期也将加入对avx的支持。

vmzy

Problem with NaCl Client
June 6, 2015 by Vijay Pande ·
We see that there is an issue with our NaCl Client (at http://folding.stanford.edu/nacl), with donors seeing this error:

Warning: Unexpected response to AS assignment request: error,DB ERROR: IO error: log.leveldb/016519.ldb: Too many open files
The server is being overloaded and our sysadmin team will take a look at it when they get back on Monday.  Long term, it looks like it’s time for us to upgrade the server this is running on since it’s getting overloaded.  We have been moving to get new servers ready for this and so getting to that should happen in about a week (servers are here and the sysadmin team has been working to getting them ready for their new roles in FAH).
大意：
NaCl服务器过载了，新设备已经就位，大概一周内进行升级。

vmzy

First full version of our Folding@Home client for Android Mobile phones
July 7, 2015 by Vijay Pande ·
We’re proud to announce the first full version of our Folding@Home client for Android Mobile phones.  This version is available to all Android Mobile phones with version 4.4 (Kitkat) and above.  Thanks to suggestions by donors we have redesigned the user interface and added new features such as:

contribute processing time continuously: just connect to a WiFi network and a charger.
one can login to Google Game Services, earn collaboration achievements, compete against his / her friends in processing time.
collaborate processing time from multiple devices under the same Google Game Services account.
settings screen has been removed. No need to configure anything!
details about the currently selected research type can be queried by touching the Research Type title on main screen, or by choosing “Active Research” on menu.
Scientifically, as in our previous beta run, we continue to focus on breast cancer with our mobile app. In this project, we’re investigating the nature of drug resistance mutations in key proteins (kinases) that are targets for breast cancer drugs. By studying the nature of how these mutations change these key drug targets, we will be able to both advance our basic biophysical understanding of these key proteins as well as build a tool to be used for patient specific breast cancer treatment— by sequencing the tumor and seeing what mutations are present, our tool seeks to recommend the best drug for a specific patient.

The beta has been a success with positive feedback from our community. We plan to add additional features in the comming months to further enhance the user interface and experience. The beta version has been downloaded more than 170,000 times worldwide, with more than 62,000 mobile phones contributing at the same time. We want to thank our community for your feedback and continued support.

We’ve also added a new movie to advertise and highlight the app.  It’s on YouTube here:http://www.youtube.com/embed/Ayjw-NTMXdo?feature=oembed
大意：
发布Android版客户端
仅支持4.4版及以上Android系统。该客户端主要研究乳腺癌蛋白变异。

vmzy

Simulating protein dynamics to find binding-competent states
July 15, 2015 by Vincent Voelz ·
Mutation to the tumor-suppressor protein p53 is a common feature in most cancers. MDM2–a protein whose job it is to downregulate p53 via their direct binding interaction–has therefore become a prime target for cancer therapeutics. Normally, a small helical region of p53 binds the MDM2 receptor site, but if a molecule with a similar shape can bind the receptor site of MDM2 strongly enough, it can prevent p53 from binding, thus making more p53 available to perform its tumor suppression abilities.

Many different kinds of molecular mimics of the p53 helix have been designed to disrupt the p53-MDM2 interaction, including stapled peptides, cyclic hairpin peptides, beta-peptides, peptoids (N-substituted oligoglycines), oligoarylamides, and spiroligomers, just to name a few. These molecules are much larger than typical small-molecule drugs, and have interesting folding properties that must be overcome to achieve tight binding. Stapled peptides, for instance, feature a hydrocarbon “staple” that helps rigidify the helical conformation in solution, which in turn enhances the binding affinity.

Using molecular simulations on Folding@home, we have been studying the coupled folding and binding of the p53 helix to MDM2 to address several key questions. One goal is to understand the roles the conformational dynamics in shaping the binding mechanism – such information can ultimately help to design better-binding molecular mimics.

Another question is whether or not molecular dynamics simulations can be used to discover binding-competent receptor conformations of MDM2 in the absence of a bound crystal structure. In new work from our lab (Pantelopulos et al. Proteins 2015), we show that ligand-free simulations of MDM2 starting from conformations with a closed binding cleft can sample open-cleft conformations capable of binding. We also tested the performance of several recent force field models in predicting experimental NMR measurements. We found that that all of the force fields perform similarly well, but that longer simulations (out to a microsecond) result in better agreement with experiment.

You can read about our work in the latest issue of Proteins:

Microsecond simulations of MDM2 and its complex with p53 yield insight into force field accuracy and conformational dynamics George A. Pantelopulos and Vincent A. Voelz. Proteins: Structure, Function and Bioinformatics, Accepted (2015)
大意：
大多数癌细胞都会释放蛋白酶使P53抑癌蛋白失效，其中最常见的是MDM2。如果能找到一种与P53螺旋结构类似的分子，与MDM2结合使它大量失效，那么P53就能发挥它的抑癌功效。虽然现在已经发现了很多这种分子，但是它们的分子结构偏大，有很多不足。
所以我们用FAH对MDM2的分子结构进行模拟。一方面试图了解构型变化对结合点生成的影响，以便将来制造更好的拟构药物。另一方面，希望了解缺少限制晶体结构的MDM2分子是否能够生成其他的结合点。在最近的模拟研究中，我们发现MDM2在没有限制的情况下，仍能生成结合点。我们在实验室对这些结合点进行了核磁共振验证。发现这些结合点都有效，而且模拟时间越长（毫秒级）结果越可靠。