Murugan N Arul, Zaleśny Robert
Department of Theoretical Chemistry and Biology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.
Department of Physical and Quantum Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wyb. Wyspiańskiego 27, PL-50370 Wrocław, Poland.
J Chem Inf Model. 2020 Aug 24;60(8):3854-3863. doi: 10.1021/acs.jcim.0c00423. Epub 2020 Aug 13.
Monoamine oxidase B (MAO-B) is a potential biomarker for Parkinson's disease (PD), a neurodegenerative disease associated with the loss of motor activities in human subjects. The disease state is associated with dopamine deprival, and so the inhibitors of MAO-B can serve as therapeutic drugs for PD. Since the expression level of MAO-B directly correlates to the disease progress, the distribution and population of this enzyme can be employed to monitor disease development. One of the approaches available for estimating the population is two-photon imaging. The ligands used for two-photon imaging should have high binding affinity and binding specificity toward MAO-B along with significant two-photon absorption cross sections when they are bound to the target. In this article, we study using a multiscale modeling approach, the binding affinity and spectroscopic properties (one- and two-photon absorption) of three (Flu1, Flu2, Flu3) of the currently available probes for monitoring the MAO-B level. We report that the binding affinity of the probes can be explained using the molecular size and binding cavity volume. The experimentally determined one-photon absorption spectrum is well reproduced by the employed QM/MM approaches, and the most accurate spectral shifts, on passing from one probe to another, are obtained at the coupled-cluster (CC2) level of theory. An important conclusion from this study is also the demonstration that intrinsic molecular two-photon absorption strengths (δ) increase in the order δ (Flu1) > δ (Flu2) > δ (Flu3). This is in contrast with experimental data, which predict similar values of two-photon absorption cross sections for Flu1 and Flu3. We demontrate, based on the results of electronic-structure calculations for Flu1 that this discrepancy cannot be explained by an explicit account for neighboring residues (which could lead to charge transfer between a probe and neighboring aromatic amino acids thus boosting δ). In summary, we show that the employed multiscale approach not only can optimize two-photon absorption properties and verify binding affinity, but it can also help in detailed analyses of experimental data.
单胺氧化酶B（MAO - B）是帕金森病（PD）的一种潜在生物标志物，帕金森病是一种与人类运动活动丧失相关的神经退行性疾病。疾病状态与多巴胺缺乏有关，因此MAO - B抑制剂可作为治疗PD的药物。由于MAO - B的表达水平与疾病进展直接相关，该酶的分布和数量可用于监测疾病发展。估计数量的可用方法之一是双光子成像。用于双光子成像的配体在与靶标结合时，应具有对MAO - B的高结合亲和力和结合特异性以及显著的双光子吸收截面。在本文中，我们使用多尺度建模方法研究了三种目前可用的用于监测MAO - B水平的探针（Flu1、Flu2、Flu3）的结合亲和力和光谱性质（单光子和双光子吸收）。我们报告说，探针的结合亲和力可以用分子大小和结合腔体积来解释。所采用的量子力学/分子力学（QM/MM）方法很好地再现了实验测定的单光子吸收光谱，并且在耦合簇（CC2）理论水平上获得了从一个探针到另一个探针时最准确的光谱位移。这项研究的一个重要结论也是证明了固有分子双光子吸收强度（δ）按δ（Flu1）>δ（Flu2）>δ（Flu3）的顺序增加。这与实验数据相反，实验数据预测Flu1和Flu3的双光子吸收截面值相似。基于对Flu1的电子结构计算结果，我们证明这种差异不能通过明确考虑相邻残基来解释（这可能导致探针与相邻芳香族氨基酸之间的电荷转移，从而提高δ）。总之，我们表明所采用的多尺度方法不仅可以优化双光子吸收特性并验证结合亲和力，还可以帮助对实验数据进行详细分析。
