A mechanism for reducing entropic cost of induced fit in protein-RNA recognition

Induced fit has been postulated to be an important component of ligand interactions with proteins, including protein-DNA interactions. We imagined that the entropic cost of induced fit might be highly dependent on the local protein sequence context around critical contact residues. To investigate this question, we analyzed the basis for active or inactive phenotypes found in a library of combinatorial sequence variants of a surface-located helix-loop peptide which is essential for the anticodon-binding activity of a class I tRNA synthetase. Molecular dynamics simulations of the domain encompassing the helix-loop peptide of the active variants consistently demonstrated fixation of the local motion of five critical (for function) residues which are highly mobile in inactive variants. Additional experiments with other rationally chosen mutants extended the correlation between phenotype and motion of these vital residues. We propose that the need for fixation of local motion is an important constraint on sequences of surface peptides which form parts of RNA-binding sites. The fixation of motion of critical residues in the unbound protein can significantly reduce the entropic cost of complex formation by induced fit.