Theoretical Investigations of Interactions of Ligands with Various Hemoproteins

描述（由申请人提供）：血蛋白在广泛的生物系统中发挥重要作用，包括氧转运和储存（血红蛋白和肌红蛋白）、氧代谢（氧化酶、过氧化物酶、过氧化氢酶和羟化酶）和电子转移（细胞色素）。这个建议是一个国家的最先进的理论研究的相互作用的几个生物相关的小分子配体与各种血红素蛋白。除了用先进的密度泛函理论（DFT）方法描述配体-血红素相互作用外，拟议的工作将模拟与蛋白质环境的相互作用。后者被认为是至关重要的各种功能的血红素蛋白，但其作用还没有得到很好的理解。它在理论研究中很少受到关注，部分原因是这样做需要大量的计算。我们建议使用混合量子力学/分子力学（QM/MM）方法来研究配体，血红素基团，以及它们与蛋白质环境的相互作用。QM治疗将使用DFT进行，增加了最近开发的色散相互作用的校正，与分子间相互作用的可靠描述（例如蛋白质环境和配体-血红素复合物之间）是可能的。将对配体、血红素和最接近的蛋白质残基进行QM处理。将使用阿姆斯特丹密度泛函（ADF）和Gaussian03软件。本文主要研究了蛋白质环境对XO分子的四个性质的影响：（1）XO分子的结构、相互作用能和结合动力学参数（2）可溶性鸟苷酸环化酶（sGC）样血红素结构域的配体选择性;（3）细胞色素P450催化循环活性中间体的结构和能量学;（4）血红素加氧酶与叠氮化物、OH和OOH物种复合物的电子结构。 血红素蛋白是包括人类在内的许多生命系统的重要组成部分。它们由两部分组成，含金属的血红素部分和蛋白质部分。拟议的工作是血红素蛋白的计算建模研究，将包括在模型中的蛋白质部分。这些结果将提供关于它们的不同蛋白质部分如何使不同血红素蛋白执行其特定功能的信息。

DESCRIPTION (provided by applicant): Hemoproteins play essential roles in a wide range of biological systems, including oxygen transport and storage (hemoglobin and myoglobins), oxygen metabolism (oxidases, peroxidases, catalases, and hydroxylases), and electron transfer (cytochromes). This proposal is for a state-of-the-art theoretical study of the interaction of several biologically relevant small-molecule ligands with various hemoproteins. In addition to describing the ligand-heme interaction with advanced density-functional theory (DFT) methodology, the proposed work will model the interaction with the protein environment. The latter is thought to be vital for the various functions of hemoproteins, but its role is not well understood. It has received little attention in theoretical studies, in part because of the large computational demands of doing so. We propose to study the ligand, the heme group, and their interaction with the protein environment using hybrid quantum mechanics/molecular mechanics (QM/MM) methodology. The QM treatment will be performed using DFT, augmented with a recently developed correction for dispersion interactions, with which a reliable description of intermolecular interactions (e.g. between the protein environment and the ligand-heme complex) is possible. The QM treatment will be performed on the ligand, heme, and the closest protein residues. The Amsterdam Density Functional (ADF) and Gaussian03 software will be used. The effect of the protein environment on four properties will be investigated: (1) The structure, interaction energy, and kinetic parameter for the binding of XO molecules (X = O, C, N) to Mb; (2) The ligand selectivity of soluble guanylate cyclase (sGC)-like heme domains; (3) The structure and energetics of the active intermediates in the catalytic cycle of cytochrome P450s; (4) The electronic structure of heme oxygenase complexes with azide, OH, and OOH species. Hemoproteins are critical components of many living systems, including humans. They consist of two parts, the metal-containing heme part and the protein part. The proposed work is a computational modeling study of hemoproteins that will include the protein part in the model. The results will provide information on how their different protein parts enable different hemoproteins to perform their specific functions.