标题:Protein Computer Games: Me Fold Pretty One Day / 蛋白质游戏:绞尽脑汁的一天
作者:Jeffrey M. Perkel
日期:2008 年 10 月 14 日
概要:简要介绍了 Foldit 蛋白质折叠游戏的情况、科学背景和未来展望。

How thousands of would-be scientists are helping a team of researchers figure out protein shapes via the Internet, and in the comfort of their own homes

By Jeffrey M. Perkel

I’m stuck—again.

I’m sitting at my computer, playing a game. It’s not a typical game: I’m using human spatial reasoning and puzzle-solving know-how to manipulate and shape virtual proteins.

The game—FoldIt—is an exercise in molecular origami. I use my mouse to tug and twist at a backbone of mottled greens, browns, oranges and reds on my screen, each color representing the properties of a particular region of the protein. Side chains, chemical pendants that make the protein’s building blocks unique, hang off the main backbone like charms on a bracelet.

Proteins are long chains of building blocks called amino acids, the specific number and arrangement of which makes each protein—whether it makes up your hair or carries oxygen in your blood—unique. In the cell, proteins fold as they are assembled, the chain (or backbone) of molecules twisting and kinking to make a structure that resembles a tangled Slinky. A protein’s shape (or structure) determines what it does, where it goes, and the molecules with which it interacts.

At the moment I’m working on a poisonous protein produced by the funnel spider. The protein is clearly unhappy: unnaturally elongated, its color palate is more angry red than green, and four atoms have been flagged as too close to one another for comfort.
现在我正在摆弄漏斗网蛛的一种毒蛋白。这个蛋白质看起来状态很不好:它被拉得太长,颜色也是表示警告的红色比绿色多,另外还有 4 个地方发生了位置上的冲突。

A few simple moves yield big dividends: From a starting score of 1,807, two quick keystrokes make the protein noticeably more compact. The atoms get their space, and the color palate has shifted toward green. My score now at 7,710, the current high score—8,649—seems within reach. Yet I’m at a loss of how to get there.
简单摆弄几下之后,情况就好多了。刚开始时我的分数是 1807,仅仅按了两个键之后蛋白质就显然变得更紧凑了。冲突不见了,颜色也变绿了。现在我的分数是 7710。目前的最高分是 8649,看起来并不像是不可逾越的,但我完全不知道从何着手。

I have a PhD in cell and molecular biology from the University of Pennsylvania, but it’s not enough. Frustrated, and with my player ranking at a dismal 430th out of 450, I give up.
我以前在宾夕法尼亚州大学拿过一个细胞和分子生物学的博士学位,但这好像对我玩好这个游戏没多大作用。最后看着我的排名停滞在 430 名(共有 450 名玩家),我还是灰溜溜地放弃了。

Having a doctorate means I know how laborious and expensive it is to determine the correct structure for a given protein in the lab. A relatively short protein of, say 100 amino acids, could assume trillions of different shapes. Only one is correct—typically the one with the lowest energy. That’s because, as University of Washington (U.W.) in Seattle biochemist David Baker explains it, a protein’s structure is like a ball on a sloping floor: It will find its lowest energy state just as the ball will naturally roll to the surface’s lowest point. Figuring out the "correct" shape of a given protein, then means finding the shape with the lowest energy level.
我在这个领域有一个博士学位,所以我很清楚在实验室里测定某个给定的蛋白质的正确结构是一项多么费劲而且昂贵的工作。即使是那些只含有大概 100 个氨基酸的蛋白质也可能有上万亿种不同的形状,而在此之中只有一种形状是正确的,就是能量最低的那种。华盛顿大学的生物化学家 David Baker 解释说,这是因为蛋白质的结构就像是在起伏不平的地面上的一个小球,会自动滚到地面上最低的地方,因为在那里它的能量最低。要找到某个给定蛋白质的正确形状就意味着要找到使蛋白质能量最低的形状。

Baker came up with an automated way to do that: Rosetta@home. Like the popular SETI@home screen saver that is used to help sift out any signal from the cosmos that may be of intelligent origin, Rosetta harnesses processing power from idle computers around the world to predict protein shapes, twisting and bending chains to try to get to the minimum energy. Sometimes, the program makes rookie mistakes. Users saw them: "I’m watching what’s going on on my computer, and these random moves the computer’s making," Baker recalls hearing, "are often just silly."
Baker 教授想到了一个全自动完成这个工作的方法:Rosetta@home。它的工作原理和著名的用于在从外太空接收的无线电波中筛选地外文明信号的 SETI@home 屏保一样,就是利用全世界计算机的闲置计算资源来预测蛋白质的形状,不停扭动和弯曲这些分子来尝试得到最低能量的状态。有时候程序会出些白痴的错误,而用户也能看见。“我正在看着屏保上的东西,计算机做的这些移动经常看起来非常笨。”Baker 回忆某个用户对他说过的话。

A colleague, David Salesin, suggested converting Rosetta@home into an interactive game. He connected Baker with Zoran Popović, a computer scientist at U.W., who in turn passed the project to his graduate student, Seth Cooper, and postdoc Adrien Treuille. The first public beta was unveiled a year later.
Baker 的一个同事,David Salesin,建议将 Rosetta@home 变成一个互动游戏。他替 Baker 联系了同在华盛顿大学的计算机科学家 Zoran Popović,后者将这个任务交给了他的一个研究生 Seth Cooper 和博士后 Adrien Treuille。一年后第一个公众测试版就面世了。

Your challenge if you download the software: to pull, push, nudge and rotate the protein, represented as a three-dimensional, multicolored pipe, into its correct shape using tools such as pull and tweak, shake and wiggle. Each structure is assigned a score: the lower the energy level, the higher the score. Introductory exercises and in-game aides like "peekaboo," which compares top-scoring solutions with yours, help novices get up to speed.

For me, there are too many options. For top-10 player (and former number one) Sirenbrian—aka Florida-based software engineer Brian Smith, who plays FoldIt a couple of hours every night—the signature move is known as the "local wiggle strategy" as well as "walking the backbone," "slice ‘n dice" or just "Brianizing". He isolates short segments of the structure and "wiggles" to lower the energy of the locked-off segment.
这么多的选择让我无所适从。前十名玩家之一,曾经是第一名的 Sirenbrian,他就有不少的动作组合。他的真实身份是佛罗里达州的一位软件工程师 Brian Smith,每晚都玩几个小时的 Foldit。他经典的动作组合有“局部 Wiggle”、“遍历骨架”、“切割”和“Brian 化”。他将整个结构的一个小片段分离出来,然后对它使用“Wiggle”工具来降低能量。

Former number one player Charles Cusack (screen name "Ferzle"; he’s now ranked 23rd), an assistant professor of computer science at Hope College in Holland, Mich., uses a very simple strategy: pull on the protein’s backbone, shake, wiggle and repeat. "You just change it a little bit," he says "then let the algorithms do their work."
曾经是第一名的玩家 Charles Cusack(昵称是“Ferzle”,现在排名 23)是密歇根州荷尔兰的霍普大学计算机科学系的助理教授,他的策略很简单:稍微拉动蛋白质的骨架,“Shake”然后“Wiggle”,然后不断重复这样的步骤。“你只需要让它稍作改变,”他说,“然后让算法解决问题。”

Staying up late playing protein-folding games may seem a lonely exercise, but chat windows, a wiki, duels and group play make FoldIt into a social environment in which users learn from each other. More than 50,000 individuals have downloaded the application since its release in May. Hundreds actively play it, both alone and in groups, with five or six new gamers joining hourly. Only about half are biologists; the others range from software engineers to historians, from grandmothers to middle-schoolers.
熬夜玩这个蛋白质折叠的游戏可能看起来有点孤独,但是装备了聊天窗口、Wiki、决斗模式和团队合作的 Foldit 已经成为了一个在线社区,玩家可以在其中互相帮助互相学习。自从五月程序公测之后,Foldit 已经有超过五万人次的下载了。通常会有几百人在线,有的单兵作战,有的团队合作,而每个小时平均会有大概五六个新玩家加入。在这些玩家中,只有一半是生物专业的,其他人从软件工程师到历史学家,从老太太到中学生都有。

There aren’t any prizes, although Baker acknowledges the winners on the FoldIt Web site. Yet for users, it’s about more than just the high score. "It is a game that feeds into the actual scientific process," Sirenbrian says. "We might be in the process of developing a new way of analyzing proteins and being of help to people." Thrianya, a grandmother of three with a high school education, says in her user profile, "I love pushing these little bits and pieces around and enjoy very much chatting with people from around the world who like the same sort of thing."
尽管 Baker 博士会在 Foldit 的网站上贴出每次优胜者的名单,但并没有任何奖品。但对于玩家来说,游戏的目的不仅仅是获得高分。“这是一个帮助推进现有科学研究进程的游戏,”Sirenbrian 说,“我们可能正在发展一种分析蛋白质的方法,这也是帮助他人的一种方式。”只有高中学历,现在是三个孩子的祖母的 Thrianya 在她的用户档案中说:“我喜欢推着这些一片片的东西玩,而我也非常喜欢跟世界各地跟我有这种相同爱好的人聊天。”

Baker and his team learn from their users, continually on the lookout for moves that users rely on. The most successful routine manipulations will ultimately be codified into Rosetta@home, to make the screen saver more effective.
Baker 博士和他的团队也从玩家惯用的招数上学了不少东西。最成功的操作方法将会被整合到 Rosetta@home 里边,令计算程序更有效。

FoldIt’s developers also fly top folders to Seattle to watch them work with the program. Sirenbrian spent a day and a half at FoldIt headquarters in early August. "They interviewed me, videotaped me playing a little bit, and we talked about some of the new tools and features I would like to see added," he says. Among his suggestions were a "squeeze" function, to compress the entire structure (more compact proteins tend to have lower energy) and the ability to control the strength of the wiggle function.
Foldit 的开发者有时候也会出钱让前几名的玩家到西雅图,然后看着他们玩游戏。在八月上旬 Sirenbrian 就在 Foldit 的总部停留过一天半。“他们采访我,将我玩游戏的情况录了像,我们还讨论了一些我想要的新工具和特性,”他说。他建议添加一个“Squeeze”功能,用以将整个结构压缩,使蛋白质更加紧致,从而能量更低。他还建议添加对“Wiggle”工具的速度限制。

One of Sirenbrian’s biggest complaints with FoldIt is that the game is short on instructions. "It is like throwing a lot of tools into the pit," he says, "and seeing what we do with them."
Sirenbrian 对 Foldit 的最严重的抱怨就是这个游戏缺乏对玩家的指导。“就像是给陷在困境中的玩家扔了一大堆的工具,”他说,“然后看我们会怎么做。”

From Baker’s perspective, however, that is precisely the point. "We don’t know a priori what the best strategies are [for folding proteins], so we create the tools and see what people do with them."
但从 Baker 博士眼中看来,这就是目的。“我们显然不清楚(折叠蛋白质的)最好策略是什么,所以我们做了一些小工具,看看人们会用它们干点什么。”

Still, U.W.’s Popović says user input has doubled the number of FoldIt tools since its initial release in May. There’s now an annotation tool, which allows users to tag a structure with notes for others to view as well as a tool that rotates structural elements.
尽管这样,Popović 说,在玩家的反馈下,Foldit 提供的工具已经比五月刚刚开始发布的时候多了一倍。现在有一个笔记工具,能让玩家在结构上挂上标签,供其他人参考,还有一个工具可以改变某个氨基酸所处的结构状态(螺旋、链状和片状)。

Soon, the developers will rely on their users’ wisdom to design totally new proteins, which FoldIt has planned for the next release, scheduled to go live sometime in October or November. The new version challenges users to design completely novel proteins that could become tomorrow’s HIV vaccines and biofuels. Baker plans to create the 10 best solutions for each challenge in his lab to see how they work.
可能很快在 Foldit 发布的下一个新版本中,开发者们会依靠玩家的智慧来设计全新的蛋白,这个新版本可能会在十月或者十一月发布。新版本给玩家的任务非常具有挑战性:设计全新的蛋白质,这些蛋白质可能会用于开发新的艾滋病疫苗或者生物燃料。Baker 博士打算在每次挑战中挑选前十名的答案来进行合成,然后看看它们的效果如何。

"We are hoping to define this whole new genre of games, that we would like to call ‘scientific discovery games,’" Popović says. "The idea is to find many different places in science where the human ability to problem solve can be directly applied without necessarily requiring somebody to get a PhD in a particular field first."
“我们希望能定义这种全新的游戏,我们将会把它称为‘科学发现游戏’,”Popović 说,“主要的想法就是在科学中寻找这样的一些问题,解决这些问题不需要人们在该领域接受博士教育,只需要动用人类解决问题的能力就行了。”



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