Structure-guided rational design of ?/?-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.

ABSTRACT: We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported ?/?-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived ?/?-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three ? residues of the original ?/? backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new ?/?-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.

SUBMITTER: Smith BJ 

PROVIDER: S-EPMC3970217 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature