Untangling life's origins

Mar 11, 2013

Researchers in the Evolutionary Bioinformatics Laboratory at the University of Illinois in collaboration with German scientists have been using bioinformatics techniques to probe the world of proteins for answers to questions about the origins of life.

Proteins are formed from chains of and fold into that determine their function. According to professor Gustavo Caetano-Anollés, very little is known about the evolutionary drivers for this folding.

In collaboration with scientists at the Heidelberg Institute for , he has been working at the interface of molecular evolution and , looking back to when proteins first appeared approximately 3.8 billion years ago to determine changes in folding speed over time.

To do this, they looked at all known protein structures as defined in the Structural Classification of Proteins (SCOP) database and mined their presence in 989 fully sequenced genomes. In a previous study, researchers in Caetano-Anollés's group used SCOP and genomic information to reconstruct phylogenomic trees that describe the history of the protein world. The current research is based on these types of trees.

"They are not the standard trees that people see in phylogenetic analysis," he said. "In phylogenetic analysis, usually the tips of the trees, the leaves, are organisms or microbes. In these, they are entire ."

In contrast, the leaves of these new trees are , which are compact evolutionary units of structure and function. Proteins are usually complex combinations of several domains.

"We have a world of about 90,000 of these structures, but they seem to be always producing the same designs," he said. Over the last 10 years, he has been part of the effort to map these designs, or folds, because they are determined by the way the protein chains fold on themselves. To date, approximately 1,300 folds have been characterized.

For the current study, the researchers identified protein sequences in the genomes that had the same folding structure as known proteins. They then used bioinformatics techniques to compare them to each other on a time scale to determine when proteins became part of a particular organism. This allowed them to map protein structures and organisms onto a timeline.

Directly calculating the folding speed for all of these proteins would be impossible with today's technology, so the researchers took advantage of the fact that a protein always folds at the same points and used a measure called Size Modified Contact Order (SMCO).

Contact order is the ability of a protein to establish links between segments of the polypeptide chain. When points that are close together on the chain come together, they generally form helical structures; when distant points come together, they form beta strands that interact with each other and form sheets. Contact order measures how many of the connections are local and how many are distant. Experimental studies have shown that it is correlated with folding speed. The measure is normalized (size modified) to take protein length, which affects folding speed, into account.

They saw a peculiar pattern in the results.

"What we see is an hourglass," said Caetano-Anollés. "At the beginning, proteins seem not to be folding so fast. And then, as time progresses, there's a tendency to fold faster and faster. And then it reaches a critical point, and at this point we have a tendency that reverses, that seems to go back again to slow folding." However, the tendency toward higher speed dominates.

This point coincides with what he calls the "Big Bang" in protein evolution. Approximately 1.5 billion years ago, more complex domain structures and multi-domain proteins emerged with the appearance of multicellular organisms. Amino acid chains, which make up proteins, also became shorter at this point in time.

Why does folding speed matter?

"If the protein does not fold, in the vast majority of cases it will not have a function. So folding implies functionality. And speed of folding implies speed of achieving that functionality," he explained. "For a cell, that's very important, because if proteins are very slow folders, there is a time lag to when that function will be accessible to the cell."

Fast folders are also less susceptible to aggregation, or clumping together, so they work faster. Moreover, proteins that fold rapidly are more likely to fold correctly. misfolding has been linked with diseases such as Alzheimer's.

Caetano-Anollés said, however, that this research makes an important contribution to understanding how molecules work. "The complexities of the biological functions of molecules are still poorly understood," he said.

"If we mix the world of molecular dynamics with the world of , we can then determine what aspects of sequences are important for molecular dynamics, and therefore, we can apply them to genetic engineering, synthetic biology, and so on."

Explore further: NYSCF Research Institute announces largest-ever stem cell repository

Related Stories

Protein origami: Quick folders are the best

Jan 31, 2013

The evolutionary history of proteins shows that protein folding is an important factor. Especially the speed of protein folding plays a key role. This was the result of a computer analysis carried out by ...

Protein folding made easy

Jun 07, 2011

Protein folding has nothing to do with laundry. It is, in fact, one of the central questions in biochemistry. Protein folding is the continual and universal process whereby the long, coiled strings of amino ...

Unfolding 'nature's origami'

Mar 02, 2009

Sometimes known as "nature's origami", the way that proteins fold is vital to ensuring they function correctly. But researchers at the University of Leeds have discovered this is a 'hit and miss' process, with proteins potentially ...

Study of giant viruses shakes up tree of life

Sep 13, 2012

A new study of giant viruses supports the idea that viruses are ancient living organisms and not inanimate molecular remnants run amok, as some scientists have argued. The study reshapes the universal family ...

Quantifying protein-folding mechanisms

Oct 15, 2012

European scientists are investigating the mechanisms by which proteins fold to form complex configurations using single-molecule experimental techniques.

Recommended for you

Crowdsourced power to solve microbe mysteries

11 hours ago

University of New South Wales scientists hope to unlock the secrets of millions of marine microbes from waters as far apart as Sydney's Botany Bay and the Amazon River in Brazil, with the help of an international ...

Reading a biological clock in the dark

Oct 21, 2014

Our species' waking and sleeping cycles – shaped in millions of years of evolution – have been turned upside down within a single century with the advent of electric lighting and airplanes. As a result, ...

User comments : 3

Adjust slider to filter visible comments by rank

Display comments: newest first

Tausch
1 / 5 (1) Mar 11, 2013
Caetano-Anollés said, however, that this research makes an important contribution to understanding how molecules work


All good. Can this research be made available? As a contribution to the advancement of not only those willing to read the research - their show of display of interest in another persons work is always welcome.
Or so the rumor goes...

Of the proteins that do not fold the minority have functions.
What is the nature of functions that utilize proteins that do not fold. Are these functions limited or specialized?
baudrunner
1 / 5 (1) Mar 11, 2013
To my mind, the only reason that proteins fold is that the process leads to more readily available binding sites on the molecule for future interaction with cellular components. The attractive and repulsive forces within the precursor molecule cause the warping and twisting of the peripheral components in order to balance forces until we get a finished product that cannot fold any more because it will have trapped itself into a special configuration. Take a completely folded protein, add an amino acid segment to it, and it will rearrange itself into a new configuration. I fail to see how studying the how and why of protein folding leads to a greater understanding of evolution, though.
Tausch
1 / 5 (1) Mar 12, 2013
leads to more readily available binding sites on the molecule for future interaction with cellular components. - b

Just the opposite.

You want binding sites that are specific. Specific to the fold.
What is 'trapped itself'?
What is 'special configuration'?
Study the how and why first. Only then can you tell yourself you failed to see.