Trylska Joanna, Tozzini Valentina, Chang Chia-en A, McCammon J Andrew
Interdisciplinary Centre for Mathematical and Computational Modeling, University of Warsaw, Warsaw, Poland.
Biophys J. 2007 Jun 15;92(12):4179-87. doi: 10.1529/biophysj.106.100560. Epub 2007 Mar 23.
We analyze the encounter of a peptide substrate with the native HIV-1 protease, the mechanism of substrate incorporation in the binding cleft, and the dissociation of products after substrate hydrolysis. To account for the substrate, we extend a coarse-grained model force field, which we previously developed to study the flap opening dynamics of HIV-1 protease on a microsecond timescale. Molecular and Langevin dynamics simulations show that the flaps need to open for the peptide to bind and that the protease interaction with the substrate influences the flap opening frequency and interval. On the other hand, release of the products does not require flap opening because they can slide out from the binding cleft to the sides of the enzyme. Our data show that in the protease-substrate complex the highest fluctuations correspond to the 17- and 39-turns and the substrate motion is anticorrelated with the 39-turn. Moreover, the active site residues and the flap tips move in phase with the peptide. We suggest some mechanistic principles for how the flexibility of the protein may be involved in ligand binding and release.
我们分析了肽底物与天然HIV-1蛋白酶的相遇、底物纳入结合裂隙的机制以及底物水解后产物的解离。为了考虑底物，我们扩展了一个粗粒度模型力场，该力场是我们之前为研究HIV-1蛋白酶在微秒时间尺度上的瓣片打开动力学而开发的。分子动力学和朗之万动力学模拟表明，肽结合需要瓣片打开，并且蛋白酶与底物的相互作用会影响瓣片打开频率和间隔。另一方面，产物的释放不需要瓣片打开，因为它们可以从结合裂隙滑向酶的侧面。我们的数据表明，在蛋白酶-底物复合物中，最大波动对应于17和39转角，并且底物运动与39转角呈反相关。此外，活性位点残基和瓣片尖端与肽同步移动。我们提出了一些关于蛋白质灵活性如何参与配体结合和释放的机制原理。
