Forti Flavio, Boechi Leonardo, Estrin Dario A, Marti Marcelo A
Department de Fisicoquimica and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.
J Comput Chem. 2011 Jul 30;32(10):2219-31. doi: 10.1002/jcc.21805. Epub 2011 May 3.
The ubiquitous heme proteins perform a wide variety of tasks that rely on the subtle regulation of their affinity for small ligands like O2, CO, and NO. Ligand affinity is characterized by kinetic association and dissociation rate constants, that partially depend on ligand migration between the solvent and active site, mediated by the presence of internal cavities or tunnels. Different computational methods have been developed to study these processes which can be roughly divided in two strategies: those costly methods in which the ligand is treated explicitly during the simulations, and the free energy landscape of the process is computed; and those faster methods that use prior computed Molecular Dynamics simulation without the ligand, and incorporate it afterwards, called implicit ligand sampling (ILS) methods. To compare both approaches performance and to provide a combined protocol to study ligand migration in heme proteins, we performed ILS and multiple steered molecular dynamics (MSMD) free energy calculations of the ligand migration process in three representative and well theoretically and experimentally studied cases that cover a wide range of complex situations presenting a challenging benchmark for the aim of the present work. Our results show that ILS provides a good description of the tunnel topology and a reasonable approximation to the free energy landscape, while MSMD provides more accurate and detailed free energy profile description of each tunnel. Based on these results, a combined strategy is presented for the study of internal ligand migration in heme proteins.
无处不在的血红素蛋白执行着各种各样的任务，这些任务依赖于它们对诸如O2、CO和NO等小分子配体亲和力的精细调节。配体亲和力由动力学缔合和解离速率常数来表征，这部分取决于配体在溶剂和活性位点之间的迁移，而这种迁移是由内部空腔或通道介导的。已经开发了不同的计算方法来研究这些过程，这些方法大致可分为两种策略：一种是成本较高的方法，在模拟过程中明确处理配体，并计算该过程的自由能景观；另一种是速度较快的方法，使用事先计算的不含配体的分子动力学模拟，然后再纳入配体，称为隐式配体采样（ILS）方法。为了比较这两种方法的性能，并提供一种研究血红素蛋白中配体迁移的组合方案，我们对三个具有代表性且在理论和实验上都有深入研究的案例进行了ILS和多次引导分子动力学（MSMD）自由能计算，这些案例涵盖了广泛的复杂情况，为本工作的目标提供了一个具有挑战性的基准。我们的结果表明，ILS能够很好地描述通道拓扑结构，并对自由能景观进行合理近似，而MSMD能够提供更准确、详细的每个通道的自由能分布描述。基于这些结果，提出了一种研究血红素蛋白内部配体迁移的组合策略。
