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体都利用的一项重要的生理优势，它可能会受到疾病的不利影响，例如最近的新冠肺炎病就是由病毒感染引起的。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，这些气味是由名为气味的小化学分子传播的。关于复杂气味检测反应的第一步，有两个相互矛盾的假设，这是由专门的嗅觉细胞中的专门受体执行的。第一种假设假设气味是以气味分子的形状编码的，它们的形状由受体的内腔识别，气味可以装入这些腔中，类似于正确的钥匙如何放入锁中。第二种假设认为气味与气味分子以特定频率振动有关，这些分子振动是由受体通过复杂的、基于量子力学的电子隧道机制探测和检测的。本项目旨在探索气味检测的振动假说，利用基于尖端量子力学的实验测量和计算模型，在没有嗅觉感受器和存在嗅觉感受器的情况下，对振动气味和隧道电子之间的相互作用进行研究。基于量子力学的振动气味和电子相互作用的建模将伴随着实验，并将澄清实验结果。这项探索性研究将大大有助于理解最基本的生物传感机制之一，并可能有助于未来开发具有近单分子检测灵敏度的人造鼻子。该项目将为培养涉及量子化学、纳米技术和生物工程的多学科领域的博士后、博士和本科生提供大量机会。这项研究将通过一系列实验和理论研究，有助于理解生物学中量子效应的前沿之一，旨在为证实或拒绝基于量子力学的嗅觉机制模型提供证据。这个模型被称为“嗅觉振动理论，VTO”，将分子的气味与它们的振动光谱联系起来，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，这一机制仍未得到证实，也存在争议。本项目将使用扫描隧道显微镜(STM)来测量在纳米结中没有和存在气味分子的情况下的隧道电流，以及隧道电流与偏置电压的关系(隧道光谱)。在该项目的第二阶段，气味将在脂质纳米盘中重新组成，这些脂质纳米盘将附着在导电表面上，用于STM测量，目的是捕捉非弹性电子隧道。此外，在隧道结中存在气味分子的情况下的非弹性隧道效应的计算研究将被用来模拟实验条件，并提供电子隧道效应的微观理解。计算的非弹性效应将被用来与实验数据进行比较，并提供关于振动模式的作用的见解。我们将用最先进的量子力学理论来研究气味分子中的非弹性电子隧穿。该项目由生物科学局分子和细胞生物科学部的分子生物物理学小组支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.