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Thanks to billions of years of evolution, enzymes make life possible by speeding up vital chemical reactions in living organisms. Finding a routine way to redesign the structure of these proteins could have wide-reaching applications across medicine and biotechnology – cutting the production costs of drugs and chemicals by making the process faster and more efficient. It could also reduce industry’s environmental impact by using biodegradable, biological enzymes instead of traditional catalysts, many of which are toxic.
Currently, however, the use of such modified enzymes remains limited. This is partly because we don’t yet fully understand how natural enzymes work, and partly because of a lack of reliable and cost-effective ways of redesigning these biological catalysts for specific purposes.
What we do know is that enzymes are highly dynamic and can fluctuate between different structures – allowing them to bind to chemicals and then release the products of the reaction. Amid this backdrop, the EU-funded DIREVENZYME project worked on developing new ways of tweaking enzyme structure using sophisticated computer models to test their approach.
Previous research has shown that introducing mutations to enzymes – by changing the sequence of amino acids that form their structure – can give them new functions and fine-tune their efficiency. Taking this further, DIREVENZYME delivered a tool to speedily determine the best mutation points for any given enzyme to enhance its activity.
‘Our main challenge was to predict which mutations in the enzyme sequence are required to favour a desired reaction or accept a non-natural substrate,’ says project coordinator Sílvia Osuna of the University of Girona in Spain. ‘To achieve this, we developed the Shortest Path Map (SPM) computing tool, which analyses different conformational states and identifies which positions of the enzyme are most important.’
Computer simulations mimic evolution
The DIREVENZYME team used computational chemistry, applying mathematical models to explore enzyme structure and study their biochemical activity.
By using a combination of Molecular Dynamics computer simulations – a method for studying the physical movement of atoms and molecules – and other models, the team managed to speed up and reduce the complexity of the enzyme redesign process.
The developed tool took amino acid sites, which had been identified as the best places to make mutations, and compared them to existing computer simulations that modelled the natural evolution of enzymes. In this way, DIREVENZYME researchers were able to provide evidence for the effectiveness of their tool. The positions identified by the new tool exactly matched the sites which mutated in the laboratory evolution experiments, showing that computers can mimic nature’s rules of evolution.
Designing new enzymes
DIREVENZYME results have greatly expanded understanding of how enzymes function to speed up reactions. Going forward, the project’s outcomes will be useful in further developing computer tools to routinely redesign enzymes for use in industry.
‘We are now validating our newly developed tool using a wide range of enzymes,’ says Osuna. ‘Our main goal is to evaluate how useful our new approach could be in designing new enzymes for industrial applications, and in a variety of related fields – such as in the design of novel carbon-based materials and novel inhibitors for liver cancer, amongst others.’