Department of Chemistry & Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
J Am Chem Soc. 2020 Mar 25;142(12):5449-5460. doi: 10.1021/jacs.9b07820. Epub 2020 Mar 13.
An important aspect of cellular function is the correct targeting and delivery of newly synthesized proteins. Central to this task is the machinery of the Sec translocon, a transmembrane channel that is involved in both the translocation of nascent proteins across cell membranes and the integration of proteins into the membrane. Considerable experimental and computational effort has focused on the Sec translocon and its role in nascent protein biosynthesis, including the correct folding and expression of integral membrane proteins. However, the use of molecular simulation methods to explore Sec-facilitated protein biosynthesis is hindered by the large system sizes and long (i.e., minute) time scales involved. In this work, we describe the development and application of a coarse-grained simulation approach that addresses these challenges and allows for direct comparison with both and experiments. The method reproduces a wide range of experimental observations, providing new insights into the underlying molecular mechanisms, predictions for new experiments, and a strategy for the rational enhancement of membrane protein expression levels.
细胞功能的一个重要方面是正确靶向和输送新合成的蛋白质。这一任务的核心是 Sec 易位子的机制，这是一种跨细胞膜转运新生蛋白质和将蛋白质整合到膜中的跨膜通道。大量的实验和计算工作都集中在 Sec 易位子及其在新生蛋白质生物合成中的作用，包括整合膜蛋白的正确折叠和表达。然而，使用分子模拟方法来探索 Sec 促进的蛋白质生物合成受到所涉及的大系统尺寸和长（即分钟）时间尺度的阻碍。在这项工作中，我们描述了一种粗粒度模拟方法的开发和应用，该方法解决了这些挑战，并允许与 和 实验直接进行比较。该方法再现了广泛的实验观察结果，为基础分子机制提供了新的见解，对新实验进行了预测，并提出了一种合理提高膜蛋白表达水平的策略。
