A Mechanism for Reducing Entropic Cost of Induced Fit in Protein−RNA Recognition

Abstract

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.

Domain motions in dihydrofolate reductase: a molecular dynamics study

“…Analysis in terms of individual modes shows that, superimposed on this, different low-frequency modes are responsible for separately coupling the adenosine-binding site and portions of the MTX-binding site. Long-range coupling between parts of proteins and the active/ ligand-binding sites of the kind observed here (regions separated by $17 A Ê ) have been observed in other simulations, both at the atomic level (Brunger et al, 1985;Leenders et al, 1994;van Aalten et al, 1995b;Depouplana et al, 1996) and at the level of domains (Komeiji et al, 1994;Luo et al, 1994).…”

Role of Dimerization in KH/RNA Complexes: The Example of Nova KH3

“…First, we observe a general stiffening of the protein upon protein dimerization. Stiffening of noninteracting regions of a protein upon interaction with nucleic acids has been proposed to be functional toward reducing the entropic cost associated with the interaction in the tRNA/aaRS (37) and GCN4/DNA (38) complexes. Second, high frequency motions still observable in the loops directly involved in RNA-binding are lost upon interaction with RNA.…”

Induced fit of a peptide loop of methionyl-tRNA formyltransferase triggered by the initiator tRNA substrate

“…(19). Therefore, although the protection of MTF by the initiator Met-tRNA N against trypsin cleavage, could, on its own, be ascribed to the tRNA shielding an otherwise unstructured and exposed region of MTF in the MTF⅐Met-tRNA N complex, the combined evidence suggests very strongly that amino acids 40-45 of MTF undergo a local conformational change in the MTF⅐Met-tRNA N complex in an inducedfit mechanism (41)(42)(43)(44). Such an induced conformational change would be akin to what happens in the HIV-1 Rev peptide-RRE (Rev response element) interactions (45) or bovine immunodeficiency virus Tat peptide-TAR RNA interactions (46,47).…”