Folding research recruits unconventional help

ORIGINAL: CELL - Current Biology

Michael Gross is a science writer based at Oxford. He can be contacted via his web page at www.michaelgross.co.uk

Summary
A denatured protein chain can find its well-ordered three-dimensional structure, the native state, in under a second, using only the information contained in the sequence. For researchers, however, the prediction of structures from sequences is a hard problem, so they are now recruiting all the help they can get, including idle computers and game consoles, game players, and little hints from evolution. Michael Gross reports.

MAIN TEXT

Protein folding is one of the miracles of nature that human technology finds quite difficult to follow. Ever since the classic ribonuclease A experiments of Christian Anfinsen in the 1960s it has been clear that the amino acid sequence of a polypeptide chain determines the unique three-dimensional folded conformation it will adopt under physiological conditions. Even though we now know that some proteins remain intrinsically disordered, and some may ‘fold around’ a ligand, it is still true that a protein's structure, and hence its function, is somehow encoded in the sequence of the amino acids. As the theoretician Cyrus Levinthal pointed out early on, there is an astronomical number of wrong conformations which the chain cannot possibly try out in a reasonable time, so there must be mechanisms that allow polypeptide chains to find the native state encoded in their sequence. Folding researchers have elucidated some of these mechanisms in the last decades, but so far haven't been able to decipher the code and therefore aren't generally able to read a sequence and predict what shape it will adopt.

An early approach to the problem was to build bigger computers dedicated to simulations of folding, a development that culminated in the development of IBM's Blue Gene, first announced in 1999 with the explicit target of tackling protein folding, but it didn't crack the prediction problem once and for all. By the turn of the millennium, computer simulations of the protein movements could only just cover a microsecond, while it was known from experimental studies that the relevant folding reactions happened on the millisecond timescale.

Folding at home

Based on that shortfall of computing power and the increasing availability of PCs connected via the internet, the group of Vijay Pande at Stanford University developed a distributed computing program called Folding@home, using the now widely adopted practice of chopping a problem into small parcels and farming them out to many computers that are online but idle (as, for instance, most computers in universities are, most of the time).

Since 2006, the lab also offers a version of the program that runs on games consoles, which enabled a dramatic increase in the processing power accessible to the program. In September 2007, the program achieved a consistent level above one petaFLOPS (10¹⁵ floating-point operations per second), as the first computing system of any kind to do so (the fastest supercomputer at the time was Blue Gene with just over a quarter of that power). In November 2011, Folding@home passed the milestone of six petaFLOPS.

Folding puzzle: The rearrangement of a linear polymer into a compact three-dimensional shape proceeds autonomously in nature but is still puzzling biochemists. (Photo: Michael Gross.)

The simulation of protein dynamics by the Folding@home software is based on the observation that protein chains populate certain free energy minima for a period of time, and then quickly move on to another minimum. Pande's group uses so-called Markov state models to find connections between these minima and map the likelihood of transitions. In 2010, the group used this approach combined with the distributed computing power of Folding@home to simulate the folding of the 39-residue protein NTL9, which takes about 1.5 milliseconds (J. Am. Chem. Soc. (2010), 132, 1526–1528). The time span of this simulation was a thousand times longer than that achieved by other methods.

Pande's group uses this approach to address a range of biomedically relevant issues around protein folding, including diseases that involve misfolded proteins (such as Alzheimer's, Parkinson's and Huntington's disease), the fundamental questions of protein folding mechanisms, and the prediction of unknown structures from sequences, which feed into commercial drug design. “Through the Folding@home distributed computing project, we have been able to muster an unparalleled computational resource for studying protein folding, allowing us to study complex systems on timescales thousands of times longer than would otherwise be possible,” says Pande. The group makes all datasets generated from the research available on request.

Folding game

Meanwhile, the group of David Baker at the University of Washington at Seattle had developed an algorithm called Rosetta for the prediction of small protein structures, and also set up distributed computing (Rosetta@home) to provide additional computing power for the prediction work. Participants who have this program installed on their computers can watch how the protein chain gradually finds its native conformation. It so happened that some participants watched the process and spotted possible arrangements that would improve the energy-efficient packing, but weren't able to interact with the program, finding themselves in the situation of someone watching a game show and shouting at their TV set.

Folding fun: Tens of thousands of online game players around the world have contributed to folding research via the game Foldit, developed at the University of Washington at Seattle. (Photo: Mohini Patel Glanz.)

This Rocking Lead Singer (Hatsune Miku) is a 3D Hologram.

ORIGINAL: Singularity Hub

October 20th, 2010 by Aaron Saenz

The internet is such a big place that sometimes I stumble onto huge trends that I’ve never even heard of before. Case in point: Hatsune Miku. She’s a Japanese pop diva who’s just started to play massive stadium concerts to sold out crowds. Her hair is blue, she dresses like Sailor Moon, and she’ll only appear in concerts via a 3D ‘hologram’. Oh, and did I forget to mention that she’s completely fictional? Created by Crypton Future Media, Hatsune Miku is a virtual singing avatar that you can purchase for your PC and program to play any song you create. She and her virtual colleagues have gone on limited tours in Japan and virtual avatar song writing is a growing trend all over the world. Surprising? Perhaps, but the thing that really blows me away is that I actually like her songs. Check out Hatsune Miku’s performance of Stargazer in the video below. Not bad for JPop.

Watching Miku sing live is pretty amazing. The 3D ‘hologram’ isn’t that impressive, it looks to be a modern version of the pepper’s ghost illusion we’ve seen before, but the crowd reaction is intense. I’ve been to concerts where the band’s fan base was considerably less enthusiastic. How must it feel to be a musician and see this virtual character getting way more love than you? Hatsune Miku and her ‘friends’ may only have played a few tours, but there’s little doubt that these guys are rock stars:

In order to create a character that sounds believably human, Crypton uses a real person’s voice as the basis for the avatar’s distinct singing style. The adaptation of someone’s singing voice into a character that a user can program to sing anything has lead to controversy. Real musicians have been loathe to step forward and submit their voices for fear that they’ll be replaced by a virtual copy of themselves. Instead of professional singers, Crypton has hired cartoon voice actors to provide the basis for their avatars. Miku is reportedly created from the voice of Saki Fujita.

The technology for Crypton’s Hatsune Miku program comes from Yamaha’s Vocaloid software which provides the means to create a realistic synthesized singing voice. You can hear samples of the raw Vocaloid synthesizer (which hasn’t been styled to fit any particular character like Hatsune Miku) on its website here. Miku and other avatars retail for ¥15,750 (~$193) and allow users to compose music and connect it to vocals note by note. You can share the songs you create via sites like Piapro (JP). Writing music for virtual avatars has become so popular that Crypton has established a music label, KarenT, and you can see many of the associated music videos for these songs on their YouTube channel.

It’s hard to quantify how large of an impact Vocaloid software is having on popular music. Yamaha doesn’t directly market the software itself, instead relying on licensed developers like Crypton (in Japan) and Zero-G (in the UK) to sell various products based on the technology. There are many sites like Piapro where users can share their work, and many simply skip forums and go straight to YouTube. There are various blogs and sites dedicated to discussing the Vocaloid phenomenon (I recommend you start with Vocaloidism), and there are karoake and music-composing video games featuring some of the most popular avatars.

It seems clear that virtual characters like Hatsune Miku are on the upward swing of their popularity. Crypton’s avatars have played several live concerts in the past year. Miku’s first ’solo’ performance took place on March 9th, and was titled Miku no Hi Kanshasai 39’s Giving Day – this is where the Stargazer performance was recorded. DVD and Blu-ray copies of the performance are set to be released globally, and there have been screenings of the concert in San Francisco and New York. The tour coincides with the release of the Hatsune Miku Project Diva video game from Sega.

Having just been introduced to the Vocaloid scene, I’m sort of in awe. Not by the quality of music – some of it is good, but mostly it’s pretty generic mainstream stuff. No, I’m impressed by the possibilities created by such virtual avatars. YouTube is already full of videos where users mix and match songs to various pieces of art, and remixing/sampling is a global music phenomenon. Now, these secondary source musicians have a whole other tool in their belt. They can have high quality virtual characters sing whatever they want. Modern technology is merging producers and consumers of art into a new being – the prosumer. Avatars like Hatsune Miku are accelerating that process, allowing us to generate more quality content on our own, and share that content with anyone via the web. In the future we will all be a part of this exchange of creative prosumerism. Ask not for whom the 3D hologram pop star sings – it sings for thee.

[image credit: Segabits]

[video credit: Miku39GivingDay]

[sources: AnimeNewsNetwork, Crypton, Vocaloidism]