Lesovoy Dmitry, Roshchin Konstantin, Sala Benedetta Maria, Sandalova Tatyana, Achour Adnane, Agback Tatiana, Agback Peter, Orekhov Vladislav
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia.
Science for Life Laboratory, Department of Medicine, Karolinska Institute, SE-171 65 Solna, Sweden.
Int J Mol Sci. 2025 Sep 12;26(18):8917. doi: 10.3390/ijms26188917.
Conformational heterogeneity is essential for protein function, yet validating theoretical molecular dynamics (MD) ensembles remains a significant challenge. In this study, we present an approach that integrates free MD simulations, starting from an AlphaFold-generated structure, with refined experimental NMR-relaxation data to identify biologically relevant holistic time-resolved 4D conformational ensembles. Specifically, we select trajectory segments (RMSD plateaus) consistent with experimental observables. For the extracellular region of PsrSp, we found that only specific segments of the long MD trajectory aligned well with experimental data. The resulting ensembles revealed two regions with increased flexibility, both of which play important functional roles.
构象异质性对蛋白质功能至关重要，但验证理论分子动力学（MD）系综仍然是一项重大挑战。在本研究中，我们提出了一种方法，该方法从AlphaFold生成的结构开始，将自由MD模拟与精细的实验NMR弛豫数据相结合，以识别生物学相关的整体时间分辨4D构象系综。具体而言，我们选择与实验观测值一致的轨迹片段（RMSD平台）。对于PsrSp的细胞外区域，我们发现长MD轨迹中只有特定片段与实验数据良好对齐。所得系综揭示了两个灵活性增加的区域，这两个区域均发挥重要的功能作用。
