Kulesza Alexander, Daly Steven, Dugourd Philippe
Univ Lyon, Université Claude Bernard Lyon 1, CNRS, Institut Lumière Matière, F-69622, Lyon, France.
Phys Chem Chem Phys. 2017 Apr 5;19(14):9470-9477. doi: 10.1039/c7cp00611j.
We have investigated the free energy landscape of Aβ-peptide dimer models in connection to gas-phase FRET experiments. We use a FRET-related distance coordinate and one conformation-related coordinate per monomer for accelerated structural exploration with well-tempered metadynamics in solvent and in vacuo. The free energy profiles indicate that FRET under equilibrium conditions should be significantly affected by the de-solvation upon the transfer of ions to the gas-phase. In contrast, a change in the protonation state is found to be less impacting once de-solvated. Comparing F19P and WT alloforms, for which we measure different FRET efficiencies in the gas-phase, we predict only the relevant structural differences in the solution populations, not under gas-phase equilibrium conditions. This finding supports the hypothesis that the gas-phase action-FRET measurement after ESI operates under non-equilibrium conditions, with a memory of the solution conditions - even for the dimer of this relatively short peptide. The structural differences in solution are rationalized in terms of conformational propensities around residue 19, which show a transition to a poly-proline type of pattern upon mutation to F19P - a difference that gets lost in the gas-phase.
我们结合气相荧光共振能量转移（FRET）实验，研究了Aβ肽二聚体模型的自由能景观。我们使用一个与FRET相关的距离坐标和每个单体一个与构象相关的坐标，通过在溶剂中和真空中的加权元动力学进行加速结构探索。自由能分布表明，在平衡条件下的FRET应受到离子转移到气相时去溶剂化的显著影响。相比之下，一旦去溶剂化，质子化状态的变化影响较小。比较F19P和野生型（WT）同种型，我们在气相中测量到它们具有不同的FRET效率，我们预测的只是溶液群体中的相关结构差异，而非气相平衡条件下的差异。这一发现支持了这样的假设：电喷雾电离（ESI）后的气相作用FRET测量是在非平衡条件下进行的，即使对于这种相对较短肽的二聚体，也保留了溶液条件的记忆。溶液中的结构差异根据残基19周围的构象倾向得到合理解释，在突变为F19P时，这些倾向显示出向多聚脯氨酸类型模式的转变——这种差异在气相中消失了。
