To rationalize the specificity of biomolecular recognition in type II non-ribosomal peptide synthesis, we analyzed interactions between two (homologous) prolyl-carrier proteins, PigG and PltL, and their cognate adenylases, PigI and PltF, respectively, using a combination nuclear magnetic resonance (NMR) spectroscopy, chemical crosslinking, mutational studies, x-ray crystallography, and molecular dynamics simulations. Interestingly, PigG demonstrates substantial cross-pathway activity, reacting with both PigI and PltF, whereas PltF exclusively undergoes reaction with its cognate adenylase. Herein, we describe computer simulations of the standalone PCP, the cognate complexes, PigG-PigI, PltL-PltF, as well as PigG-PltF. These simulations provide a time-resolved understanding of interfacial interactions and implicate differences in the loop region of the carrier proteins as responsible for specificity.

A tale of two carrier proteins: Computer simulations reveal the basis of carrier protein specificity in type II non-ribosomal biosynthesis

ACS Fall 2021

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