EAGER: Exploring the Quantum-Mechanical Basis of Odorant Detection by Olfactory Receptors

嗅觉是包括人类在内的许多生物利用的一项重要生理优势，它可能受到疾病的不利影响，例如由病毒感染引起的疾病，例如最近的COVID-19疾病。然而，生物体能够检测和区分数千种不同气味的机制目前尚不清楚，这些气味是由称为气味剂的小化学分子传播的。关于复杂气味检测反应的第一步，有两种相互竞争的假设，这是由专门的嗅觉细胞中的专用受体进行的。第一种假设认为，气味是以气味分子的形状编码的，气味分子的形状是由感受器的内部腔体识别的，就像一把正确的钥匙可以锁在锁里一样。第二种假设认为，气味与气味分子在特定频率上的振动有关，这些分子的振动被受体通过复杂的、基于量子力学的电子隧道机制探测和检测到。本项目旨在探索气味检测的振动假说，利用前沿的量子力学为基础的实验测量和计算模型，在没有和存在嗅觉受体的情况下，振动气味剂和隧道电子之间的相互作用。基于量子力学的振动气味剂和电子之间相互作用的建模将伴随实验，并将澄清实验结果。这项探索性研究将极大地有助于理解最基本的生物传感机制之一，并可能有助于未来具有接近单分子检测灵敏度的人造“鼻子”的发展。该项目将为培养涉及量子化学、纳米技术和生物工程等多学科领域的博士后、博士和本科生提供充足的机会。本研究将通过一系列的实验和理论研究，为确认或否定基于量子力学的嗅觉机制模型提供证据，从而有助于理解量子效应在生物学中的一个前沿领域。这个被称为“嗅觉振动理论”的模型将分子的气味与其振动光谱联系起来，并假设气味识别涉及电子通过气味结合受体的量子力学非弹性隧穿。然而，这一机制尚未得到证实，也存在争议。本项目将使用扫描隧道显微镜（STM）来测量纳米结中没有和存在气味分子时的隧道电流，以及隧道电流对偏置电压的依赖关系（隧道光谱）。在项目的第二阶段，气味剂将在脂质纳米盘中重组，该纳米盘将附着在导电表面上，用于STM测量，旨在捕获非弹性电子隧道。此外，在隧道结中存在气味分子时的非弹性隧道的计算研究将用于模拟实验条件并提供对电子隧道的微观理解。计算的非弹性效应将用于与实验数据的比较，并提供对振动模式的作用的见解。非弹性电子隧穿通过气味分子将研究与最先进的量子力学形式。该项目由生物科学理事会分子和细胞生物科学部分子生物物理集群支持。该奖项反映了美国国家科学基金会的法定使命，并通过基金会的智力价值和更广泛的影响审查标准进行了评估，认为值得支持。

The sense of smell is a significant physiological advantage exploited by many organisms including humans and it may be adversely affected by illnesses, such as caused by viral infections as exemplified recently by the COVID-19 disease. Yet, the mechanism by which organisms are able to detect and differentiate between thousands of different odors, which are transmitted by small chemical molecules named odorants, is currently not known. There are two competing hypotheses regarding the first steps in the complex odorant detection reaction, which is carried out by dedicated receptors in specialized olfactory cells. The first hypothesis assumes that odors are encoded in the shape of odorant molecules and their shapes are identified by receptors’ interior cavities into which odorants fit similar to how a correct key fits into a lock. The second hypothesis considers that smell is related to odorant molecules vibrating at specific frequencies and these molecular vibrations are probed and detected by receptors through a complex, quantum mechanics-based electron tunneling mechanism. This project aims at exploring the vibrational hypothesis of odor detection by exploiting cutting edge quantum-mechanics based experimental measurements and computational modeling of the interaction between vibrating odorants and tunneling electrons in the absence and presence of olfactory receptors. Quantum mechanics-based modeling of the interaction between vibrating odorants and electrons will accompany experiments and will clarify the experimental results. This exploratory research will significantly contribute to an understanding of one of the most fundamental biological sensing mechanisms and may help in future developments of artificial “noses” with near single-molecule detection sensitivity. The project will provide ample opportunities for training of postdoctoral, PhD and undergraduate students in multidisciplinary fields involving quantum chemistry, nanotechnology and bioengineering.This research will contribute to the understanding of one of the frontiers of quantum effects in biology with a set of experimental and theoretical investigations aimed at providing evidence confirming or rejecting the model of Quantum Mechanical-based olfaction mechanism. This model, known as the “Vibrational Theory of Olfaction, VTO” relates molecules’ scent to their vibrational spectra and postulates that odor recognition involves quantum mechanical inelastic tunneling of electrons through the odorant-bound receptor. However, this mechanism has remained unproven and controversial. This project will use scanning tunneling microscopy (STM) to measure the tunneling current in the absence and presence of odorant molecules in the nano-junction as well as the dependence of the tunneling current on the bias voltage (tunneling spectroscopy). In the second phase of the project, Odorants will be reconstituted in lipid nanodiscs that will be attached to a conductive surface for STM measurements aimed at capturing inelastic electron tunneling. In addition, computational studies of the inelastic tunneling in the presence of odorant molecules in the tunneling junctions will be used to model the experimental conditions and to provide microscopic understanding of electron tunneling. The inelastic effects calculated will be used to compare with experimental data and provide insight on the roles the vibrational modes. Inelastic electron tunneling through odorant molecules will be studied with state-of-the-art quantum mechanical formalism. This project is supported by the Molecular Biophysics cluster of the Molecular and Cellular Biosciences Division in the Directorate for Biological SciencesThis award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.