Computational Studies of Biomolecular Structure and Function

许多重要的生物学过程，如信号传递、识别和运输，以及感染和免疫反应，都涉及多肽或蛋白质与脂质之间的相互作用。目前，在脂双层提供的各向异性和化学复杂的环境中，很难阐明多肽和蛋白质的结构，这阻碍了对这些过程的详细描述。由于这些原因，膜蛋白的结构研究通常使用洗涤剂分子，它模仿脂双层的化学性质来溶解蛋白质，使它们更容易结晶。然而，目前还没有通用的方法用于膜蛋白结构的实验测定，这突显了可靠预测算法的必要性。了解生物分子结构和功能的有效方法是使用计算机模拟，但目前这些研究的范围受限于研究蛋白质和多肽在脂类中的折叠和自组装所需的较长时间尺度。在这项建议中，我们将通过结合我们实验室开发的新采样算法和加拿大计算公司授予我们的大量计算资源来解决这些限制。这些非同寻常的资源使我们处于独特的地位，可以在四项不同但互补的研究中检查多肽和蛋白质与脂肪和洗涤剂分子的相互作用。在其中两个项目中，我们将研究脂类和洗涤剂自组装如何溶解蛋白质并确定它们的折叠。相反，在另外两项研究中，我们将研究多肽的自组装如何影响膜蛋白的结构。这项工作将为迫切需要的膜蛋白结构预测提供先进的计算工具，并将有助于改进基于洗涤剂的方法来从实验上阐明膜蛋白的结构。同样重要的是，拟议的研究将使人们从根本上深入了解抗菌肽作用的分子基础，以及与疯牛病和慢性消耗性疾病有关的普恩蛋白多肽的毒性，这两种疾病对加拿大野生动物和农业构成严重威胁。

Many important biological processes, such as signalling, recognition, and transport, as well as infection and immune response, involve interactions between peptides or proteins and lipid. The detailed characterization of these processes is currently impeded by the difficulty in elucidating the structure of peptides and proteins in the anisotropic and chemically complex environment provided by lipid bilayers. For these reasons, structural studies of membrane proteins often employ detergent molecules, which mimic the chemical properties of lipid bilayers, to solubilize the proteins, making them more amenable to crystallization. However, at present there are no general methods for the experimental determination of membrane protein structure, underscoring the need for reliable predictive algorithms. A powerful approach to gain insight into the structure and function of biomolecules is to use computer simulations, but the scope of these studies is currently limited by the long time scales required to investigate the folding and self-assembly of proteins and peptides in lipid.In this proposal, we will address these limitations by combining novel sampling algorithms developed in our laboratory with massive computational resources awarded to us by Compute Canada. These extraordinary resources put us in a unique position to examine the interaction of peptides and proteins with lipid and detergent molecules in four different but complementary studies. In two of these projects, we will study how lipid and detergent self-assemblies solvate proteins and determine their fold. Reciprocally, in the other two studies, we will examine how the self-assembly of peptides affects the structure of lipid bilayers.This work will provide advanced computational tools for the much-needed prediction of membrane protein structure, and will help improve detergent-based approaches to elucidate the structure of membrane proteins experimentally. Just as important, the proposed studies will afford fundamental insight into the molecular basis for the action of antimicrobial peptides and the toxicity of peptides derived from prions implicated in "mad cow" and chronic wasting diseases, two serious threats to Canadian wildlife and agriculture.