Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265, 34136 Trieste, Italy.
The Abdus Salam International Centre for Theoretical Physics (ICTP), Str. Costiera, 11, 34151 Trieste, Italy.
J Phys Chem Lett. 2021 Jan 14;12(1):65-72. doi: 10.1021/acs.jpclett.0c03182. Epub 2020 Dec 11.
We analyzed a 100 μs MD trajectory of the SARS-CoV-2 main protease by a non-parametric data analysis approach which allows characterizing a free energy landscape as a simultaneous function of hundreds of variables. We identified several conformations that, when visited by the dynamics, are stable for several hundred nanoseconds. We explicitly characterize and describe these metastable states. In some of these configurations, the catalytic dyad is less accessible. Stabilizing them by a suitable binder could lead to an inhibition of the enzymatic activity. In our analysis we keep track of relevant contacts between residues which are selectively broken or formed in the states. Some of these contacts are formed by residues which are far from the catalytic dyad and are accessible to the solvent. Based on this analysis we propose some relevant contact patterns and three possible binding sites which could be targeted to achieve allosteric inhibition.
我们采用了一种非参数数据分析方法来分析 SARS-CoV-2 主蛋白酶的 100 μs MD 轨迹，该方法可以同时描述数百个变量的自由能景观。我们确定了几种构象，当动力学过程访问这些构象时，它们可以稳定几百纳秒。我们明确地描述了这些亚稳态。在这些构型中的一些中，催化偶联是不太容易接近的。通过合适的配体稳定它们可能会导致酶活性的抑制。在我们的分析中，我们跟踪了在这些状态下选择性断裂或形成的残基之间的相关接触。这些接触中的一些是由远离催化偶联的残基形成的，并且可以与溶剂接触。基于此分析，我们提出了一些相关的接触模式和三个可能的结合位点，这些位点可以作为变构抑制的靶点。
