Photochemistry in the Membrane: Quantum Chemical Studies of Fluorophores In Situ

一些最令人兴奋的细胞图像来自于荧光研究，其中绿色荧光蛋白(GFP)已经被连接到感兴趣的生物分子上。这类研究的影响是不可否认的，但较小的荧光团会更具侵入性，可能会更忠实地报道分子环境。理想情况下，新荧光团的开发应该建立在对膜环境中分子的光化学的基本原理的理解之上。这项提议采用了量子化学/选定的亚空间依赖时间的密度泛函理论的最新进展(由共同申请者之一贝斯利博士开创)，并将其应用于一系列分子和分子环境，最终在膜的原子模型中研究5-羟基Tritophan和截断的di-9-ANEPPS：两个新出现的特别感兴趣的光学探测器。该项目提出了几个计算挑战。电子激发态的计算，即使是在孤立的分子上，通常也不是微不足道的。将分子环境显式地纳入激发态计算是一项相对较新的工作，我们建议通过开发TDDFT的新发展来扩展该方法，以突破目前的限制(在原子和电子数量方面)。应用量子化学方法研究生物过程无疑是一个在不久的将来将迅速增长的研究领域。结合新的实验，这将提供对许多生物和医学过程的详细和定量的洞察。我们建议使用最先进的量子化学方法通过计算荧光团的基态和激发态来研究分子和膜之间的相互作用。这些计算应该能够建立分子-膜相互作用的详细图像，并为这些令人兴奋的新实验以及最终我们对膜界面生物过程的理解提供定性的见解。

Some of the most thrilling images of cells come from fluorescence studies, in which green fluorescent protein (GFP) has been attached to biomolecule of interest. The impact of such studies is undeniable, but smaller fluorophores would be less invasive and potentially more faithful reporters of the molecular environment. The development of new fluorophores should ideally be built on a first principles' understanding of the photochemistry of molecules in membrane environments. This proposal takes recent advances in quantum chemistry / selected subspace time-dependent density functional theory (pioneered by, Dr Besley, one of the co-applicants) / and will apply it to a series of molecules and molecular environments, culminating in the study, in an atomistic model of a membrane, of 5-hydroxytrytophan and truncated di-9-ANEPPS: two optical probes of particular emerging interest.This project poses several computational challenges. Electronic excited state calculations, even on isolated molecules, are often not trivial. The incorporation of the molecular environment explicitly into the excited state calculations is a relatively new undertaking, and we propose to extend the approach beyond current limitations (in terms of numbers of atoms and electrons) by exploiting new developments in TDDFT.The application of quantum chemical methods to study biological processes is without doubt an area of research that will grow rapidly in the near future. In conjunction with novel experiments, this will provide detailed and quantitative insight into many biological and medical processes. We propose to use state-of-the-art quantum chemical methods to study the interaction between molecule and membranes through calculations of both the ground and excited states of the fluorophore. These calculations should enable a detailed picture of the molecular-membrane interaction to be established and provide qualitative insight into these exciting new experiments and ultimately our understanding of biological processes at the membrane interface.