A solvation induced ring puckering effect in fluorinated prolines and its inclusion in classical force-fields

Abstract

Strategic incorporation of fluorinated prolines can accelerate folding and increase thermal stability of proteins. It has been suggested that this behavior emerges from puckering effects induced by fluorination of the proline ring. We use electronic structure calculations to characterize the potential energy surface (PES) along puckering coordinates for a simple dipeptide model of proline and its fluorinated derivatives.Comparison of gas phase and implicit solvent calculations shed light on the effect of solvation on electronic structure and conformational preferences of the ring. This effect is unknown in the context of prolines, however, recently reported for furanoses in carbohydrates. The PES based on implicit solvent is then utilized to construct a correction for a classical force-field. The corrected force-field accurately captures the experimental conformational equilibrium including the coupling between ring puckering and cis-trans isomerism in fluorinated prolines. This method can be extended to other rings and substituents besides fluorine.