Computational Modeling of Conformer Stability in Benenodin-1, a Thermally Actuated Lasso Peptide Switch

Benenodin-1 is a thermally actuated
lasso peptide rotaxane switch
with two primary translational isomers that differ in the relative
position of the residue Gln15. The conversion from one conformer to
the other involves substantial enthalpy–entropy compensation:
one conformer is energetically favored and the other is entropically
favored. Here, we take a multi-scale quantum mechanical (QM) and classical
molecular dynamic (MD) approach to reveal residue-specific sources
of these differences in stability. QM reveals that the two benenodin-1
conformers involve distinct hydrogen bonding networks, with the enthalpically
favored conformer having more intra-peptide hydrogen bonds between
the Gln15 side chain and nearby residues. The evaluation of configurational
entropy over the MD-sampled geometries reveals that the entropically
favored conformer has enhanced conformational flexibility. By computing
the by-residue-sum entropies, we identify the role of Gln15 and neighboring
Glu14 in mediating the entropic variation during the switching process.
These computational insights help explain the effects of Glu14Ala
and Gln15Ala mutations on the conformational population of benenodin-1
observed experimentally.