Ivano Bertini and Gabriele Cavallaroa describe how bioinformatics is being used to make sense of the growing amounts of experimental data on the role ofmetals in biological systems

Bioinformatics is a central discipline in modern life sciences aimed at describing the complex properties of living organisms starting from large-scale data sets of cellular elements such as genes and proteins. For this wealth of information to provide useful biological knowledge, databases and software tools for data collection, analysis and interpretation are needed.

Recently there have been several advances in the design and implementation of bioinformatics resources devoted to the study of metals in biological systems, a research field traditionally at the heart of bioinorganic chemistry. Metal ions are essential constituents of living organisms. They play a role in fundamental processes from signalling and gene expression to catalysis. The function of many proteins depends critically on binding to specific metals, such as copper, iron, zinc or molybdenum. These proteins include metallothionein, crucial in maintaining the body's equilibrium and in detoxification processes, metallochaperones, which protect and direct metal ions through the cell, and extracellular proteins albumin and transferrin, essential for metal transport in human blood. Metal ions are also responsible for controlling the expression of these proteins in cells. 

Bioinorganic chemistry plays a significant role in the challenge of studying whole living systems. This ambition has recently been boosted by the development of technologies such as genomics and proteomics producing virtually complete lists of key cellular components. But in order for bioinorganic chemistry to effectively contribute to modern biology, it must focus on determining the total metal content of living organisms, from the measurement of metal concentrations to the identification of all the individual metal species. This evolution into an information-rich discipline creates a strong, constructive link with bioinformatics, which is fundamental to manage and make sense of the huge amount of biological data continuously produced in biological research.  

Bioinformatics is crucial in the support of bioinorganic chemistry databases

Bioinformatics is a relatively mature field, but its overlap with bioinorganic chemistry has been scarce, possibly due to difficulty in encoding the peculiar properties of metal species in a form suitable for computer analysis. Today, the growing awareness of the role of metals in cell physiology and disease are stimulating the creation of bioinformatics tools and resources centred on metals and metalloproteins. 

Using bioinformatics, a protein's amino acid sequence can be used to predict whether it binds to a metal, and also which metal. These methods are based on the recognition of two different signatures diagnostic for metal binding, known as domains and structures, and are most accurate when the two signatures are used in combination. Currently this technique is limited to detecting proteins bearing a sequence similar to already known metalloproteins but alternative approaches based on neural networks capable of overcoming such limitations are fast becoming available. Applying these methods to all the proteins encoded in the genome of an organism, it is possible to predict all the metalloproteins of that organism (its metalloproteome) in a metal-specific manner. Such predictions are quite valuable as experimental techniques for metalloproteomics are not yet routinely available.

Functional information for metalloproteins of known structure can also be deduced using bioinformatics. Identifying structural similarity with known metal-binding sites can then provide key hints about protein function, and the structural and chemical parameters used to make up the 'fingerprint' of the site can be varied. In some methods this description includes not only the protein residues that coordinate the metal, but also those in the immediate surroundings, which are important in modulating metal function.

Bioinformatics is crucial in the support of bioinorganic chemistry databases, which lie at the heart of modern biology, forming the infrastructure for the collection, maintenance and provision of biological information. A classification of all known metal-binding sites based on these   structural fingerprints could provide the framework for a comprehensive database on metalloproteins.

Finally, bioinformatics is central to the construction of descriptive and predictive models for cellular processes using interaction network diagrams as a platform. The development of methods and tools to integrate the information regarding metals and metalloproteins into such models in the most useful and efficient way is another foreseen benefit of the marriage between bioinformatics and bioinorganic chemistry, which will provide a major help to describe how inorganic elements are framed within living cells and achieve a deeper understanding of living systems.

Read more in the review 'Bioinformatics in bioinorganic chemistry' in Metallomics.

Enjoy this Instant insight? Spread the word using the 'tools' menu on the left or add a comment to the Chemistry World blog.