Sequence-Dependent Base-Stacking Stabilities Guide tRNA Folding Energy Landscapes

Citations Over TimeTop 16% of 2013 papers

Abstract

The folding of bacterial tRNAs with disparate sequences has been observed to proceed in distinct folding mechanisms despite their structural similarity. To explore the folding landscapes of tRNA, we performed ion concentration-dependent coarse-grained TIS model MD simulations of several E. coli tRNAs to compare their thermodynamic melting profiles to the classical absorbance spectra of Crothers and co-workers. To independently validate our findings, we also performed atomistic empirical force field MD simulations of tRNAs, and we compared the base-to-base distances from coarse-grained and atomistic MD simulations to empirical base-stacking free energies. We then projected the free energies to the secondary structural elements of tRNA, and we observe distinct, parallel folding mechanisms whose differences can be inferred on the basis of their sequence-dependent base-stacking stabilities. In some cases, a premature, nonproductive folding intermediate corresponding to the Ψ hairpin loop must backtrack to the unfolded state before proceeding to the folded state. This observation suggests a possible explanation for the fast and slow phases observed in tRNA folding kinetics.

Related Papers

• → Prediction of protein-folding mechanisms from free-energy landscapes derived from native structures(1999)393 cited
• → Stability constraints and protein evolution: the role of chain length, composition and disulfide bonds(2005)64 cited
• → Interplay between native topology and non-native interactions in the folding of tethered proteins(2013)17 cited
• → Critical nucleation size in the folding of small apparently two‐state proteins(2004)31 cited
• → Shape of the Free Energy Barriers for Protein Folding Probed by Multiple Perturbation Analysis(2006)13 cited