Issue 7, 2010

The functional capacity of the natural amino acids for molecular recognition

Abstract

We tested the functional capacity of the natural amino acids for molecular recognition in a minimalist background of binary Tyr/Ser diversity. In phage-displayed synthetic antibody libraries, we replaced either Tyr or Ser with other residues. We find that Tyr is optimal for mediating contacts that contribute favourably to both affinity and specificity, but it can be replaced by Trp, which contributes favourably to affinity but is detrimental to specificity. Arg exhibited a limited capacity for mediating molecular recognition but was less effective than either Tyr or Trp, and moreover, was the major contributor to non-specific interactions. Nine other residue types (Phe, Leu, Ile, Asn, Thr, Pro, Cys, Ala, and Gly) were found to be ineffective as replacements for Tyr. By replacing Ser with Gly or Ala, we found that Gly is as effective as Ser for providing conformational flexibility that allows bulky Tyr residues to achieve optimal binding contacts, while Ala is less effective but still functional in this capacity. For some antigens, high affinity antibodies could be derived using only Tyr/Ser/Gly diversity, but for others, additional chemical diversity was required to achieve high affinity. Our results establish a minimal benchmark for the generation of synthetic antigen-binding sites with affinities comparable to those of natural antibodies. Moreover, our findings illuminate the fundamental principles underlying proteinprotein interactions and provide valuable guidelines for engineering synthetic binding proteins with functions beyond the scope of natural proteins.

Graphical abstract: The functional capacity of the natural amino acids for molecular recognition

Supplementary files

Article information

Article type
Paper
Submitted
19 Jan 2010
Accepted
26 Mar 2010
First published
09 Apr 2010

Mol. BioSyst., 2010,6, 1186-1194

The functional capacity of the natural amino acids for molecular recognition

S. Birtalan, R. D. Fisher and S. S. Sidhu, Mol. BioSyst., 2010, 6, 1186 DOI: 10.1039/B927393J

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements