A new study investigating the binding affinities and specificity of natural amino acids for molecular recognition leads the way for engineering new proteins for therapeutic applications.   

In order to produce antibodies with improved therapeutic functions it is essential to understand the make up of the proteins. To achieve this amino acids within a protein can be swapped with another and the resulting protein interactions compared. In particular synthetic antibodies with man-made binding sites have proved to be a powerful tool in exploring molecular recognition as they allow for controlled design. Therefore there is a great demand for affinity reagents to investigate these protein interactions.

Shachdev Sidhu at the University of Toronto, Canada and colleagues at Genentech Inc, San Francisco, USA have looked directly at the role of single amino acids for affinity and specificity in protein interactions. Using phage-displayed synthetic antibody libraries, either tyrosine or serosine were replaced with other residues to investigate the role of the different amino acids as either a contact or conformation residue. 'Up until now, we could only address how the different amino acids contribute to molecular recognition using in silico analysis of proteins, and only inferences could be drawn' explains Sidhu, 'in contrast, our article provides direct, experimental evidence.'

From the twelve residues tested, tyrosine, serosine and glycosine were enough to produce high affinity antibodies against some antigens. 'It is remarkable how important tyrosine is relative to other side chains for antibody recognition,' comments James Wells, an expert in protein engineering at the University of California, San Francisco adding that 'the challenge now will be to see if this [methodology] can be generalized to other protein-protein interfaces besides the antibody scaffold.' 

Sidhu and collaborators are now using the data to design better libraries of synthetic antibodies and other proteins, and adds that 'this research will have major impacts on our ability to design better antibodies and proteins for therapeutics and other applications.'

Leanne Marle 

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