Sequence-structure-function relationships in human visual photopigments

人类视觉色素中的氨基酸突变会损害色觉或导致退行性致盲等疾病。人类视觉需要这些由发色团和相关视蛋白组成的色素，它们在不同的杆状和锥状光感受器群体中具有不同的峰值光谱灵敏度。峰光谱灵敏度由发色团类型和视蛋白的氨基酸序列决定。了解视蛋白的单个突变如何导致视觉功能异常和疾病，将有助于开发分子水平的治疗策略。目前还没有这样的理解。提出的研究的总体目标是通过使用最先进的建模方法解开光导循环的奥秘，开发新的分子水平治疗策略来治疗人类视力缺陷。这项研究的目标是建立在我们的分子建模框架上，开发和测试一个自动化的计算管道，以估计Rh1棒状视蛋白的峰值光谱灵敏度，并用它来阐明疾病相关突变的机制。在Aim 1中，我们将建立一个基于机器学习的管道，该管道将利用同源性建模和分子动力学模拟，准确预测视蛋白氨基酸序列数据的峰值光谱灵敏度。目标2将采用混合量子力学/分子力学模拟来阐明谱移的分子机制并改进管道。在Aim 3中，我们将使用管道来确定异常视觉功能的分子机制。这项提议的研究在人类视觉领域具有很高的影响潜力，因为它将为几十年来一直难以捉摸的视觉色素提供一种预测建模方法。这种对视觉色素分子功能的基因组到现象组的新理解将为设计适合于光遗传学的色素的新策略或开发靶向治疗策略铺平道路。

Amino acid mutations in human visual pigments can impair color vision or lead to diseases such as degenerative blinding condition. Human vision requires that these pigments, consisting of a chromophore and associated opsin protein, have distinct peak spectral sensitivities in separate rod and cone photoreceptor populations. Peak spectral sensitivity is determined by the chromophore type and the amino acid sequence of the opsin. Understanding how a single mutation in the opsin protein can lead to anomalous visual function and disease would assist the development of molecular-level therapeutic strategies. Such an understanding is currently not available. The proposed research has an overarching goal of developing novel molecular-level therapeutic strategies to treat human vision deficiencies by unraveling the mysteries of the phototransduction cycle using state-of-the-art modeling approaches. The goal of the proposed research is to build on our molecular modeling framework to develop and test an automated computational pipeline to estimate peak spectral sensitivity for Rh1 rod opsins and use it to elucidate mechanisms for disease-associated mutations. In Aim 1, we will build a machine-learning-based pipeline, which will utilize homology modeling and molecular dynamics simulation, for accurately predicting peak spectral sensitivity from opsin amino acid sequence data. Aim 2 will employ mixed quantum mechanics / molecular mechanics simulations to elucidate molecular mechanisms of spectral shift and improve the pipeline. In Aim 3, we will use the pipeline to determine molecular mechanisms for anomalous visual functions. The proposed research has the potential for high impact in the field of human vision because it will provide a predictive modeling approach for visual pigments, that has remained elusive for decades. This new genome-to-phenome understanding of the molecular function of visual pigments will pave the way for novel strategies to engineer pigments suitable for optogenetics, or to develop targeted therapeutic strategies.