DEVELOPMENT OF A MULTI-SCALE CHEMICAL MODELING APPROACH TO HEME-CONTAINING ENZY

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 含铁血红素蛋白在许多生物系统中发挥核心作用，结合小分子进行运输，促进电子传递和细胞凋亡。其活性位点的明显简单性使这些系统成为结构-功能研究的理想选择。 然而，它们也因存在多个氧化态（Fe II，亚铁态，Fe III，三价铁态和Fe IV，铁离子）以及多个自旋态而变得复杂。 例如，铁血红蛋白I在结合过氧化氢（H2 O2）时可以以双重态（一个未配对电子）或四重态（三个未配对电子）存在，甚至可以在从结合复合物到化合物I（铁离子）的过程中在两种状态之间转换。 显然，使用计算方法来描述机制（从而构建详细的结构-功能关系）将需要精确的电子结构方法。然而，除了晶体结构之外，对合理结构进行采样的能力对于充分理解这样的系统也是至关重要的。 对替代结构进行采样的最有效方法是通过采用经典分子力学（MM）力场的模拟（分子动力学（MD）或蒙特卡罗（MC））。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Iron-containing heme proteins play a central role in many biological systems; binding small molecules for transport and facilitating electron transfer and apoptosis. The apparent simplicity of their active sites makes these systems ideal for structure-function studies. Yet, they are also complicated by the existence of multiple oxidation states (FeII, the ferrous state, FeIII, the ferric state and FeIV, the ferryl ion) as well as multiple spin states. For example, the ferric Hemoglobin I upon binding hydrogen peroxide (H2O2) could exist as a doublet (one unpaired electron) or a quartet (three unpaired electrons) and may even convert between the two states as it progresses from the bound complex to compound I (the ferryl ion). Clearly, using computational methods to describe the mechanism (and hence construct a detailed structure-function relationship) will require accurate electronic structure methods. Yet, the ability to sample plausible structures besides the crystal structure is also crucial to a full understanding of such systems. The most efficient way to sample alternative structures is through simulations (molecular dynamics (MD) or Monte Carlo (MC)) that employ classical molecular mechanics (MM) force fields.