Theoretical Investigations of Interactions of Ligands with Various Hemoproteins

描述（由申请人提供）：血红蛋白在广泛的生物系统中发挥重要作用，包括氧运输和储存（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）。这一建议是对几种生物相关的小分子配体与各种血红蛋白相互作用的最新理论研究。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。后者被认为对血红蛋白的各种功能至关重要，但其作用尚不清楚。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）方法研究配体、血红素基团及其与蛋白质环境的相互作用。QM处理将使用DFT进行，并辅以最近开发的弥散相互作用校正，从而可以可靠地描述分子间相互作用（例如蛋白质环境与配体-血红素复合物之间的相互作用）。QM处理将在配体、血红素和最接近的蛋白质残基上进行。将使用Amsterdam Density Functional （ADF）和Gaussian03软件。研究了蛋白质环境对四种性质的影响：(1)XO分子（X = O， C， N）与Mb结合的结构、相互作用能和动力学参数；(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催化循环中活性中间体的结构和能量学；(4)叠氮化物、OH和OOH的血红素加氧酶配合物的电子结构。

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.