Influence of an Ionic Liquid on TRP-Cage Structure and Xaa-Pro Dipeptide Conformational Sampling

Abstract

Room temperature ionic liquids (RTILs) demonstrate great promise for the selective control of protein structure and function, however the fundamental aspects of RTIL effects on peptides and proteins remain unclear. Here we describe some recent results for the influence of the RTIL 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl) imide ([C4mpy][Tf2N]) on the structure of the miniprotein Trp-cage and on the behavior of Xaa-Pro dipeptides, where Xaa is any of the common amino acids. Starting from an unfolded configuration, we find that Trp-cage folds in water at 298 K in less than 500 ns of molecular dynamics (MD) simulation, but exhibits very little mobility in the RTIL at the same temperature, which is related to the RTIL viscosity. However, in simulations carried out at 365 K, the mobility of the RTIL is increased and initial stages of Trp-cage folding are observed. We employed scaled MD to expedite sampling, and demonstrate that Trp-cage in the RTIL can closely approach the aqueous folded state. While the RTIL is found to restrict Trp-cage motion, cis/trans isomerization of peptide bonds involving proline occur that are not observed in aqueous simulations. Therefore, we studied Xaa-Pro dipeptides in several environments, including the same RTIL, water, octanol, and vacuum, in order to further explore this effect. The RTIL is found to restrict Ramachandran space sampling of the dipeptides, and for Trp-Pro, isomerization of the dipeptide bond to the cis state is observed. This suggests that RTILs can be used to stabilize otherwise infrequently observed dipeptide conformations. Our simulations imply that stacking of the Trp ring and Pro ring in the cis state versus the trans state might contribute to this effect for the Trp-Pro dipeptide.