Solvation Induced Ring Puckering Effect in Fluorinated Prolines and Its Inclusion in Classical Force Fields

Area of Science:

• Computational chemistry and biophysics
• Protein structure and stability

Background:

• Fluorinated prolines are known to accelerate protein folding and enhance thermal stability.
• This effect is hypothesized to arise from puckering modifications within the proline ring due to fluorination.

Purpose of the Study:

• To investigate the potential energy surface (PES) of proline and its fluorinated derivatives along puckering coordinates.
• To elucidate the impact of solvation on the electronic structure and conformational preferences of fluorinated proline rings.
• To develop an improved computational model for predicting protein conformational behavior.

Main Methods:

• Electronic structure calculations were employed to characterize the PES of proline and fluorinated proline dipeptide models.
• Gas phase and implicit solvent models were used to assess solvation effects.
• A corrected classical force field was constructed using the implicit solvent PES.

Main Results:

• Significant shifts in puckering trends were observed between gas phase and implicit solvent calculations, highlighting the role of solvation.
• A previously unrecognized solvation-induced puckering effect in prolines was identified.
• The corrected force field accurately reproduced experimental conformational equilibria, including coupled ring puckering and cis-trans isomerism in fluorinated prolines.

Conclusions:

• Solvation plays a critical role in modulating the conformational preferences of fluorinated proline rings.
• The developed computational method accurately captures the behavior of fluorinated prolines and can be extended to other systems.
• This work provides a foundation for designing peptides and proteins with enhanced stability and folding properties.