Computational Studies of Biomolecular Structure and Function

许多重要的生物学过程，如信号传导、识别和转运，以及感染和免疫应答，都涉及肽或蛋白质与脂质之间的相互作用。这些过程的详细表征目前受到阻碍的困难，在阐明的各向异性和化学复杂的环境中提供的脂质双层的肽和蛋白质的结构。由于这些原因，膜蛋白的结构研究通常采用去污剂分子，其模拟脂质双层的化学性质，以溶解蛋白质，使其更易于结晶。 然而，目前还没有通用的方法用于膜蛋白结构的实验测定，强调需要可靠的预测算法。 深入了解生物分子的结构和功能的一种强有力的方法是使用计算机模拟，但这些研究的范围目前受到研究脂质中蛋白质和肽的折叠和自组装所需的长时间尺度的限制。 在这项提案中，我们将通过将我们实验室开发的新颖采样算法与加拿大计算机公司授予我们的大量计算资源相结合来解决这些限制。 这些非凡的资源使我们处于一个独特的位置，在四个不同但互补的研究中研究肽和蛋白质与脂质和洗涤剂分子的相互作用。 在其中两个项目中，我们将研究脂质和洗涤剂自组装如何溶解蛋白质并确定其折叠。反过来，在另外两项研究中，我们将研究肽的自组装如何影响脂质双层的结构。 这项工作将为急需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去污剂的方法，以实验方式阐明膜蛋白的结构。 同样重要的是，拟议的研究将提供基本的洞察力的抗菌肽的作用和毒性的肽从朊病毒牵连在“疯牛病”和慢性消耗性疾病，两个严重威胁加拿大野生动物和农业的分子基础。

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.