Andrea Rinaldi

The protein folds how Rosetta predicts

A promising computational method for predicting protein folding, called Rosetta, has been developed by David A. Baker and co-workers (Howard Hughes Medical Institute, Chevy Chase, MD, USA), and their colleagues at the University of Washington (Seattle, WA, USA). The correct prediction of the 3D structure of a folded protein ab initio (i.e. starting from only the amino acid sequence) has been a long-pursued problem for computational biologists. However, during the fourth Critical Assessment of Techniques for Protein Structure Prediction (CASP4), held at the Asilomar Conference Center (California, CA, USA) from 3–7 December 2000, Rosetta proved strikingly successful in deducing protein structures from linear sequences of amino acids. Rosetta functions by searching for the lowest overall energy combination of the conformations adopted by the local segments of a protein during folding, taking the distribution of conformations observed for short sequence segments in known protein structures as an approximation. Considering the wealth of raw gene sequence data being continuously produced by genome sequencing efforts, the possible implications of an ab initio computational technique such as Rosetta are far reaching, as Baker underlined ‘…one can conceive of going through a genome and generating structures and possibly functional insights for every protein’. AR(http://www.hhmi.org/news/baker.html; http://www.hhmi.org/research/investigators/bakerd.html)

A green light glows on copper disorders research.

The complete genome of Arabidopsis thaliana – the first from the plant kingdom – is now in our hands. Expectations are that this discovery will also benefit fields not directly related to plant genetics and crop production. Human health could be one of these fields. This hope is fueled by the discovery that many of the Arabidopsis genes show a significant similarity to genes involved in human disease syndromes. In some cases, the human genes are more similar to the Arabidopsis homologues than to the genes of yeast, Drosophila, or Caenorhabditis elegans. Included in this group are the genes implicated in Wilsons and Menkes diseases, two disorders of copper homeostasis [Nature (2000) 408, 823–826]. The defective functioning of the membrane-bound copper-transporting P-type ATPases that are coded by these genes, leads to copper deficiency (Menkes) or copper accumulation (Wilson). Of the two conditions, Menkes is by far the worst, being usually fatal in childhood. Researchers at Deakin University (Burwood, Victoria, Australia) led by Julian Mercer, together with colleagues from Melbourne University (Melbourne, Victoria, Australia), are studying Menkes protein structure and function, and trying to understand why different mutations of the Menkes gene give rise to the diverse aspects of the disease. Experimental efforts are also directed at understanding how deleterious Menkes effects can be over-run on a genetic and molecular level. Study strategies include the transfection of cells from Menkes patients with healthy Menkes genes, and the manipulation of the Wilsons gene (which is normal in Menkes patients), to act as a surrogate for the defective Menkes gene.(http://www.research.deakin.edu.au/research_stories)

Strengthening biotech alliance for data sharing

The coalition of biotechnology, pharmaceutical and computer companies known as Interoperable Informatics Infrastructure Consortium (I3C) is attracting new members. The consortium was established earlier this year with the goal of developing an open platform to enable researchers to share data about genomics and proteomics using the Java programming language and the XML Internet standard for data exchange. Representatives from IBM, Millennium Pharmaceuticals and Accenture were among the new members who recently joined founders Sun Microsystems, TimeLogic, Blackstone, Incogen, LabBook, Oracle and the National Cancer Institute. The new consortium, which includes, among its academic and public-sector participants, the European Bioinformatics Institute and Manchester University, was launched at the BIO 2001 conference in San Diego, USA (24–27 June). If the I3C address the challenge successfully, common standards will be set for manipulating data from several different sources over the Internet. This will particularly aid the efforts of smaller companies that have difficulty coping with the raging number of existing applications based on particular operating systems. Members of the coalition agreed that all standards coming out of the project will be fully public. AR(http://news.ft.com/home/uk)

New Framework programme goes up 17 per cent

The budget for a new Framework programme for the European Union has been boosted by a 17 percent increase over that allocated to the previous programme. The proposals for this new programme, to be run between 2003 and 2006, were presented on 21 February 2001 by research commisioner Philippe Busquin. Genomics and biotechnology that are of benefit to the health industry lay among the key priorities on which the financial resources, totalling EUR17.5 billion, will be concentrated. While praising the important raise in funding, which will permit Europe to catch up with the research budget increase just announced by the USA, many members of the European Parliament also highlighted the necessity to recruit more young people to research. AR(http://dbs.cordis.lu/news/en/home.html)

Smart as a frog

Studies in frogs have demonstrated for the first time the in vivo induction of defense peptides in a vertebrate. The soft, scale-less skin of frogs, coupled with the moist, warm environments inhabited by these amphibians, is an ideal breeding ground for microbial pathogens. The skin glands of frogs provide relief from this onslaught by secreting an array of structurally diverse peptides with antibiotic activity. A research group led by Maurizio Simmaco and Donatella Barra at the University of Rome ‘La Sapienza’ (Italy) now shows that the synthesis of antimicrobial peptides in the skin of Rana esculenta is, in fact, stimulated by microorganisms [FASEB J.(2001) 10.1096/fj.00-0695fje]. Frogs kept in a sterile environment did not produce antimicrobial peptides; however, exposure to even a single type of microorganism (one which contributes to the frogs natural flora) was sufficient to elicit a marked production of these peptides. In support of this observation, the secretions of frogs kept in bacteria-containing water (but not of those kept under sterile conditions) contained NF-κB-binding activity; a characteristic previously associated with the production of antimicrobial peptides. These findings will help researchers learn more about the molecular mechanisms governing the role of peptide antibiotics in the innate immune system. AR

A new phase for protein structures

Structural biologists determine the atomic structure of a protein by blasting the crystal with a beam of X-rays, followed by long weeks spent decoding the scattering pattern that results. However, physicist Veit Elser of Cornell University (Ithaca, NY, USA) is developing new computer algorithms that will significantly speed up the analysis of scattering data. The concept addresses the problem of measuring the phases of X-rays emerging from a sample: current X-ray diffraction methods measure the amplitude of the Fourier components of the electron density, but give no more information about the phases. Phase information would greatly help to decipher the pattern of the scattering data, and Elser hopes to find a way to identify, with the aid of computers, the phase pattern that corresponds correctly to the measured amplitudes.(http://www.news.cornell.edu/Chronicles)

Playing with RNA molecules

Scientists at the University of California (Berkley, CA, USA) have developed a technique to study the folding and unfolding of single RNA molecules using mechanical force. Carlos Bustamante and colleagues attached each end of three different types of RNA molecules: a simple RNA hairpin, an RNA molecule containing a three-helix junction, and the P5abc domain of the Tetrahymena thermophila ribozyme, to a microscopic plastic bead [Science (2001) 292, 733–737]. A piezoelectric actuator was then used to supply the force needed to unfold the molecule and the intensity of this force was measured by a laser beam. The rates of folding and unfolding of the single RNA molecules, and the positions of their transitions states along the reaction coordinate, were thus determined. AR(http://www.hhmi.org/news/bustamante.html).

Get a random move on

Randomness might be the ultimate explanation of several chemomechanical energy conversions in molecular and cellular biology. Ronald Fox and Mee Hyang Choi from the Georgia Institute of Technology (Atlanta, Georgia, USA) have reanalysed measured data for the motion of the kinesin motor protein along microtubules with a new perspective [Phys. Rev. E (2001) 63, 051901]. Kinesins ‘travel’ along microtubules while undergoing an ATP-activated attachment–detachment cycle coordinated by binding sites on microtubules. The new study revealed that what first appeared to be a concerted motion might instead be a ‘rectified Brownian movement’, a form of random motion powered by thermal energy. The model implies that, in this case, the metabolic free-energy currency of ATP does no mechanical work directly, this instead being done by thermal energy. Fox and Choi argue that, in kinesin, ATP performs a switching role, changing the protein conformation and its binding affinity. The randomness of the thermal Brownian motion is thus harnessed and constrained by conditions created by the ATP switching, resulting in a net-directed kinesin motion along the microtubule. AR(http://gtresearchnews.gatech.edu/newsrelease/KINESIN.html)

Getting organized to exploit the human proteome

Private companies are currently flexing their muscles, preparing to grasp the profits associated with completion of the human proteome, the complete set of all proteins encoded by our genome. Myriad Genetics (Salt Lake City, Utah, USA), Hitachi (Tokyo, Japan) and Oracle (Redwood Shores, California, USA) have recently (4th April) announced their formation of ‘a landmark alliance to map the human proteome in less than three years’. Valued at

Networking proteome people

185 million, the collaboration will be based at the newly formed Myriad Proteomics, a subsidiary of the project-leading company Myriad Genetics. Hitachi and the computer giant Oracle will provide the necessary computing hardware and software, respectively. Competition for Myriad Genetics was declared on 26th April when GeneProt, a relatively new Swiss biotech company, inaugurated the worlds largest facility dedicated to proteomics research in Geneva. The company is backed by thepharmaceutical giant Novartis and byCompaq, the American computer manufacturer that is also providing advanced supercomputing systems to analyze the huge volumes of data generated. According to the companys reports, the facility in Geneva has ‘51 of themost advanced mass spectrometers running around the clock searching for proteins that could become tomorrows blockbuster agents’. GeneProt, whose headquarters are moving from Switzerland to the US later this year (a second facility is also being planned for Princeton, New Jersey, USA), aims to become one of the major players in the exploitation of the commercial potential associated with proteomics. These initiatives have ignited hot debates about the potential danger of private consortiums controlling so much vital information. However, there is also skepticism about the technical capabilities of these companies to deliver their promises as the proteome is considered a much trickier target than the genome. AR(http://www.myriad.com/20010404.html; http://www.geneprot.com/scripts/press/press_e.asp)