Atomic level computer prediction has been combined with natural selection to help design highly specific drugs.
There has been more collaboration among researchers since 2008, when an artificial enzyme for catalysing a chemical reaction was first designed.
The stage for closer collaboration between computer protein design specialists and experimental biochemists was set at a recent European Science Foundation (ESF) conference.
The conference drew inspiration from the 2008 design of an enzyme from scratch that speeded-up the Kemp Elimination reaction by up to 100,000 times.
In Kemp Elimination, a proton is extracted from a carbon atom, in a reaction for which the enzyme is not actually found in nature but involves the element upon which life is rooted.
It sets the stage for the future design of enzymes that have applications in production of drugs and also non-medicinal branches of biotechnology, such as brewing and food processing.
This is according to Jiri Damborsky, chair of the ESF conference, from Masaryk University in the Czech Republic.
Damborsky also said: 'The way to move forward involves a mix of rational design and directed evolution.' The process may start with computer models to generate a molecular design for a protein with structure and function as close as possible to a desired target.
Although progress has been made with such de novo design, current models do not take account of some of the finer physical aspects of molecules and their behaviour, such as dynamics and bonding with ions in solvents, and also the exact geometry of the structure.
Differences in scale as small as a few picometers (1/100 the diameter of a hydrogen atom) can make a significant difference to the action of an enzyme.
So even though a computer can design a protein with atomic precision, it still has to be fine-tuned, which can only be achieved in a laboratory.
This is why de novo design of proteins requires collaboration between experimentalists and theoreticians.
The next step is a process to refine the designed protein.
Evolutionary mutation must be mimicked to create a diverse range of closely related molecules in the hope that one will have the right structure.
This process, known as directed evolution, creates many variants of the original protein.
Selection or screening must then be applied to this collection to identify the molecule closest to the target.
Damborsky added: 'Screens enable the researcher to identify and isolate high-performing mutants by hand, while selections automatically eliminate all non-functional mutants.' Whichever method is used, it is unlikely that any of the mutants produced in the first round of directed evolution will yield a protein with all the desired properties of the target.
Therefore, this two-step round of directed evolution is repeated several times until no further improvement can be made.
Damborsky added: 'In these experiments, the 'winners' of the previous round are diversified in the next round to create a new library.' Even after many rounds, the perfect molecule cannot usually be made.
Research needed to create this perfect molecule was discussed at the ESF conference.
One problem is that even when an apparently successful mutant has been created, it may not be stable.
This means the protein does not fold properly, becoming stuck in some half way conformation and being unable to reach its final structure.
In nature, evolution solves this problem through molecules called chaperones, which assist with the folding process, helping overcome kinetic obstacles on the way to reaching the final functional conformation.
Damborsky said chaperones were being used in some experiments to stabilise mutant proteins and enable them to fold properly into their functional structure.
However, progress needs to be made in understanding the link between the structure of a protein and its functions and how enzymes move around inside the cell.
The first of these is needed to design proteins that have the right structure for a desired function, and the second to make drugs that reach their target efficiently.
More needs to be learnt about how enzymes operate in cells and the detailed mechanisms involved in biosynthesis of proteins and their subsequent movements or interactions.
The agenda set for a follow up ESF conference includes artificial life (creating novel organisms by mimicking selective processes of nature on a larger scale).
This follow-up conference will focus on the aim of designing the ultimate artificial enzyme, capable of catalysing biochemical reactions almost at will.
The ESF conference 'Protein Design and Evolution for Biocatalysis' was held in Sant Feliu de Guixols, Spain in October 2008.
