Alchemical simulations are versatile tools for prediction of relative free energy differences. The accuracy of these methods depends critically on sampling of orthogonal (non-alchemical) degrees of freedom. Here we apply the flying Gaussian method to accelerate orthogonal degrees of freedom in peptide bond cis/trans isomerisation. The approach is demonstrated on prediction of pKa value of N-acetylproline. Isomerization of the amide bond was accelerated in this simulation by multiple orders of magnitude. Alchemical free energy was obtained by reweighting. The results show that a combination of alchemical and flying Gaussian simulations is suitable for systems with high ($\sim$ 60 kJ/mol) energy barrier.

炼金术模拟是用于预测相对自由能差异的多功能工具。这些方法的准确性主要取决于正交（非炼金术）自由度的采样。在这里，我们应用飞行高斯方法来加速肽键顺式/反式异构化的正交自由度。该方法在预测N-乙酰脯氨酸的pKa值方面得到证明。在此模拟中，酰胺键的异构化速度提高了多个数量级。炼金术的自由能通过重新加权获得。结果表明，将炼金术和飞行高斯模拟相结合适用于具有较高（$〜$ 60 kJ / mol）的势垒。