Key Laboratory of magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Mol Sci. 2019 Jul 15;20(14):3476. doi: 10.3390/ijms20143476.
As a member of the fatty acids transporter family, the heart fatty acid binding proteins (HFABPs) are responsible for many important biological activities. The binding mechanism of fatty acid with FABP is critical to the understanding of FABP functions. The uncovering of binding-relevant intermediate states and interactions would greatly increase our knowledge of the binding process. In this work, all-atom molecular dynamics (MD) simulations were performed to characterize the structural properties of nativelike intermediate states. Based on multiple 6 μs MD simulations and Markov state model (MSM) analysis, several "open" intermediate states were observed. The transition rates between these states and the native closed state are in good agreement with the experimental measurements, which indicates that these intermediate states are binding relevant. As a common property in the open states, the partially unfolded α2 helix generates a larger portal and provides the driving force to facilitate ligand binding. On the other side, there are two kinds of open states for the ligand-binding HFABP: one has the partially unfolded α2 helix, and the other has the looser β-barrel with disjointing βD-βE strands. Our results provide atomic-level descriptions of the binding-relevant intermediate states and could improve our understanding of the binding mechanism.
作为脂肪酸转运蛋白家族的一员，心脏脂肪酸结合蛋白 (HFABP) 负责许多重要的生物学活动。脂肪酸与 FABP 的结合机制对于理解 FABP 的功能至关重要。揭示与结合相关的中间状态和相互作用将极大地增加我们对结合过程的了解。在这项工作中，进行了全原子分子动力学 (MD) 模拟，以表征天然中间状态的结构特性。基于多个 6 μs MD 模拟和马尔可夫状态模型 (MSM) 分析，观察到了几个“开放”的中间状态。这些状态与天然封闭状态之间的跃迁率与实验测量值非常吻合，这表明这些中间状态与结合相关。作为开放状态的共同特性，部分展开的 α2 螺旋产生了更大的入口，并提供了驱动力来促进配体结合。另一方面，配体结合的 HFABP 有两种开放状态：一种具有部分展开的 α2 螺旋，另一种具有松散的 β-桶，βD-βE 链分离。我们的结果提供了与结合相关的中间状态的原子水平描述，并可以提高我们对结合机制的理解。
