尿素转运蛋白通透机制的理论研究

尿素是生命过程中重要的有机小分子。"尿素的跨细胞膜转运"需要特定的膜蛋白协助；这些膜蛋白中，有一类家族分布最广，称为"尿素转运蛋白"。近年来，尿素转运蛋白的通透性质受到了国际上越来越多的关注。但现有的文献均为实验方面的工作，尚无理论（模拟）文章探究尿素转运蛋白通透性的物理机制。本项目拟运用分子动力学模拟方法，从原子水平上深入研究dvUT（一种典型的、现在唯一已知三维结构的尿素转运蛋白）通透性的物理机制。主要研究内容为：在dvUT的核心区域- - "选择性过滤区域"（狭长的一维通道，长约16埃）内，尿素分子的特性（结构、结合位点、输运性质和动力学行为），尿素分子穿越该区域的自由能剖面，以及该区域"选择性通透（过滤）"的物理机制。本项目的研究可以使我们比较透彻地理解为什么尿素转运蛋白dvUT对尿素分子具有高渗透性和高度的选择性，并为理解其它种类的尿素转运蛋白的通透机制提供借鉴。

Urea is ubiquitous in nature and important to many biological processes. Urea's permeation across biological membranes is facilitated by specific membrane proteins, with the most widely distributed family called urea transporters (UTs). The permeability of UTs has recently attracted increasing attentions due to its biological importance. However, all the existing literature are from the experimental perspective; a theoretical investigation toward a detailed and quantitative understanding of the physical mechanism of UT's permeability is still lacking. In this project, we will use molecular dynamics simulations to explore the physical mechanism of permeability of dvUT (urea transporter from the bacterium Desulfovibrio vulgaris) with atomic detail. In the present study, we choose dvUT for two reasons: i) it is the only UT whose crystal structure is available; ii) it is a typical UT since its amino-acid sequence resembles that of the kidney urea channels. The central region of dvUT pore is the so-called "selectivity filter", which is a constricted channel of ~ 16 ? long, and can accommodate several dehydrated urea molecules in single file. The selectivity filter is the focus of this study. Our investigation consists of three topics: unique properties of urea in the constricted channel (including the structure of one-dimensional urea wire, urea's binding sites, the permeation properties and kinetics of urea), free-energy profile of urea's permeation across selectivity filter, and physical basis of selectivity of dvUT. This study will provide a detailed understanding toward physical basis of dvUT's high permeability and selectivity for urea, and provide useful insights into the mechanism for other UTs.