Public Solves Protein Structure -retroviral protease

[Guest guest]

Original abstract from *Nature Structural & Molecular

Biology* - see below.

~jvr

``````

http://bit.ly/qUlmyr

TheScientist

Magazine of the Life Science

News & Opinion

Public Solves Protein Structure

Players of an online game that allows users to adjust

how proteins are folded have solved a decade-long

protein structure mystery.

By Jef Akst | September 18, 2011

A small group of diverse individuals living on at least

three continents, who call themselves The Contenders,

have solved the structure of a protein that has stumped

scientists for more than 10 years. And they did so from

the comfort of their own homes, playing on online protein

folding game called Foldit.

The Contenders’ solution and its validation were

published today (September 18) in Nature Structural and

Molecular Biology.

“This is the real deal,” said biophysicist Rhiju Das of

Stanford University, who was not involved in the work. “I

think this paper really shows how this is a new way of

doing science that is more powerful than what a handful

of experts could do.”

The protein in question was a retroviral protease of the

Mason-Pfizer monkey virus, which causes an AIDS-like

disease in monkeys. Over the last decade, many

researchers had tried a variety of techniques to

determine the protein’s structure, but kept coming up

empty handed. “This viral protein…has really evaded the

efforts of expert crystallographers and the very best

automated tools,” Das said.

So one frustrated scientist, Mariusz Jaskolski of A.

Mickiewicz University in Poland and the Polish

Academy of Sciences, turned to an online game called

Foldit. The program was designed by computation

biologist Baker of the University of Washington as

an extension to his Rosetta@home program, which

allows Baker to use home computers around the world

to do complex calculations on protein structures. While

the program ran, users would see a screen saver of the

computations, Baker said, and before long, he began to

get some emails about how the program wasn’t always

accurate. “The protein, when it’s folding up its helix, is

going left when should be going right,” users reported.

So Baker designed Foldit to allow users to alter the

course of Rosetta calculations, and try to solve protein

structures on their own. The goal: fold up the protein so

it has the lowest energy, just as molecules tend to do in

real life.

In the past year and a half, users of the program had

demonstrated their potential to solve real protein-folding

problems, Baker said, so when Jaskolski came to him

with this enigmatic viral protease, they decided to put

the gamers to the test. Baker posed the problem to the

Foldit players, and watched the responses flood in.

About 600 players from 41 teams submitted more than

1.25 million solutions. Narrowing those down to 5,000,

Jaskolski and colleagues subjected them to a

computational technique called molecular replacement

(MR), which tests the models against X-ray

crystallography data. For MR to work, the proposed

structure has to be very close to accurate, in which

case the MR calculations can help perfect the details.

But previous attempts at MR for this protein had failed

because the protein models were too far off the mark.

But The Contender’s proposed protein structure was a

winner. “When we took [their] model, it was a beautiful

fit to the X-ray data so we knew [they] had solved it,”

Baker said. “We were just totally blown away. This is

the first time that a long-standing scientific problem has

been solved by Foldit players, or to my knowledge, any

scientific gaming participants.”

The final breakthrough came from Foldit user mimi, a

member of The Contenders and a science technician at

a high school near Manchester, UK, who has been

playing Foldit for about 3 years. She “tucked in a flap” of

the protein that was sticking out, she explains, to make

the protein more “globular.” But she emphasizes that

“the achievement was very much a group effort,” noting

that it wasn’t possible for her to tuck in the flap until

others in the group had made their key adjustments to

the protein’s structure.

“It’s kind of an unprecedented case of using computing

non-specialists to solve a longstanding scientific

problem,” said Wlodawer, chief of the

Macromolecular Crystallography Laboratory at the

National Cancer Institute.

The next step might be to provide Foldit users with

experimental validation as they play the game, said

Das, a former postdoc in Baker’s lab. In this case, the

players simply kept tweaking the structure until it

produced a low energy score, but didn’t get an

experimental feedback until the very end.

“What if the players do have access to experimental

data?” Das wondered. “Can they interpret it in the same

way that scientists do? Can we turn 10,000 or 100,000

into citizen scientists into real scientists who are

developing hypotheses and then doing experiments and

then refining their hypotheses?” If so, Foldit users may

not only be able to solve protein structures, but actually

refine the rules of the game itself, Das added, and help

scientists reach the ultimate goal of understanding

structure directly from a protein’s amino acid sequence.

“Predicting protein folding just on the basis of the

sequence of the protein is one of those unresolved

scientific problems,” Wlodawer said. “But these new

methods that Dr. Baker is introducing, and a few others,

are now changing this whole thing.”

F. Khatib et al., “Crystal structure of a monomeric

retroviral protease solved by protein folding game

players,” Nature Structural & Molecular Biology,

doi:10.1038/nsmb.2119, 2011.

````````````

The abstract in *Nature Structural & Molecular Biology*

is very short:

http://bit.ly/poJFhQ

NATURE STRUCTURAL & MOLECULAR BIOLOGY

BRIEF COMMUNICATION

Crystal structure of a monomeric

retroviral protease solved by protein

folding game players

Firas Khatib, DiMaio, Seth , Maciej

Kazmierczyk, Miroslaw Gilski, Szymon Krzywda, Helena

Zabranska, Iva Pichova, , Zoran

Popovic', Mariusz Jaskolski & Baker

Nature Structural & Molecular Biology (2011)

doi:10.1038/nsmb.2119

Received 27 May 2011 Accepted 08 July 2011 Published

online 18 September 2011

Following the failure of a wide range of attempts to solve

the crystal structure of M-PMV retroviral protease by

molecular replacement, we challenged players of the

protein folding game Foldit to produce accurate models

of the protein. Remarkably, Foldit players were able to

generate models of sufficient quality for successful

molecular replacement and subsequent structure

determination. The refined structure provides new

insights for the design of antiretroviral drugs.