Strategic incorporation of fluorinated prolines can lead to faster folding and stable proteins

A single atom substitution in a proline residue of ribonuclease A can lead to accelerated folding into its 3D structure with increased thermostability. It has been suggested that this can be caused by stereo-electronic effects due to fluorination of amino acids. In this work we use quantum chemistry and QM/MM methods coupled with accelerated sampling to study the static and dynamic properties of proline containing peptides in water, with a focus on the effect of fluorination on the free energy surface and conformational properties. We compare the free energy surfaces of plain vs fluorinated dipeptides along the amide dihedral and the proline ring pucker reaction coordinates to examine the effect of fluorination. Finally, we characterize the important interactions in the system: namely intramolecular H-bonding, n -> pi* and gauche interactions in the presence of explicit solvent. We find that the experimental data can be understood from the change in the dihedral potential surface due to electronic structure differences due to fluorination. The impact of this on the conformational properties of peptides and self-assembly in solution is discussed.