Zielinski Kara A, Dolamore Cole, Wang Harrison K, Henning Robert W, Wilson Mark A, Pollack Lois, Srajer Vukica, Hekstra Doeke R, Dalton Kevin M
School of Applied and Engineering Physics, Cornell University, Ithaca, New York 14853, USA.
Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA.
Struct Dyn. 2024 Nov 6;11(6):064301. doi: 10.1063/4.0000269. eCollection 2024 Nov.
Time-resolved x-ray crystallography (TR-X) at synchrotrons and free electron lasers is a promising technique for recording dynamics of molecules at atomic resolution. While experimental methods for TR-X have proliferated and matured, data analysis is often difficult. Extracting small, time-dependent changes in signal is frequently a bottleneck for practitioners. Recent work demonstrated this challenge can be addressed when merging redundant observations by a statistical technique known as variational inference (VI). However, the variational approach to time-resolved data analysis requires identification of successful hyperparameters in order to optimally extract signal. In this case study, we present a successful application of VI to time-resolved changes in an enzyme, DJ-1, upon mixing with a substrate molecule, methylglyoxal. We present a strategy to extract high signal-to-noise changes in electron density from these data. Furthermore, we conduct an ablation study, in which we systematically remove one hyperparameter at a time to demonstrate the impact of each hyperparameter choice on the success of our model. We expect this case study will serve as a practical example for how others may deploy VI in order to analyze their time-resolved diffraction data.
同步加速器和自由电子激光的时间分辨X射线晶体学（TR-X）是一种很有前景的技术，可在原子分辨率下记录分子动力学。虽然TR-X的实验方法已经大量涌现并日臻成熟，但数据分析往往很困难。提取信号中微小的、随时间变化的改变常常是从业者面临的瓶颈。最近的研究表明，当通过一种称为变分推断（VI）的统计技术合并冗余观测值时，这一挑战可以得到解决。然而，时间分辨数据分析的变分方法需要确定成功的超参数，以便最佳地提取信号。在本案例研究中，我们展示了VI在一种酶DJ-1与底物分子甲基乙二醛混合后随时间变化的成功应用。我们提出了一种从这些数据中提取电子密度中高信噪比变化的策略。此外，我们进行了一项消融研究，即一次系统地去除一个超参数，以证明每个超参数选择对我们模型成功的影响。我们希望这个案例研究能为其他人如何部署VI以分析他们的时间分辨衍射数据提供一个实际范例。
