Solution studies of interacting polymer systems in biology

我的研究重点是生物物理技术在分析超浓缩（AUC）和相关的生物物理解决方案技术领域的进步。AUC是胶体材料表征的首选方法。这一领域的进展有利于生物化学、物理学和材料科学的基础研究，并为生物制药和合成聚合物化学等行业提供了改进的表征工具。对于生物聚合物和其他纳米材料，AUC提供了在生理条件下研究分子及其组装的能力，其中pH值，离子强度，还原电位，温度和其他因素很容易调节。作为新的加拿大150生物物理学研究主席，我最近成立了加拿大流体动力学中心，这是一个首屈一指的实验室，配备了三个非常独特的AUC仪器，以加速加拿大的生物物理研究。这种工具组合在其他任何地方都不可用，利用这些仪器的独特功能，我们拟议研究的目标是通过开发新的分析协议和软件工具来推进以前的努力，使我们能够解决以下四个领域的长期挑战：**1。膜蛋白（MP）。MP是生物学上重要的分子，但由于其在水性溶剂中的溶解性差而难以研究。我们将嵌入MP在定义明确的含有生理磷脂的纳米盘，并表征形成的复合物。使用具有独特消光特征的荧光团的差异标记，我们希望清楚地区分空纳米盘和嵌入的MP，它们的寡聚化状态，以及它们与靶标的相互作用，以及错误折叠和聚集的MP。2.聚合系统（AS）。由于其过度的异质性和缺乏胶体/化学稳定性，AS的研究具有挑战性。我们将专注于候选药物与淀粉样蛋白的相互作用-研究它们对破坏或溶解有害淀粉样蛋白寡聚体或抑制其形成的影响。我们将利用新仪器大大增强的扫描速度和多速沉降来获得高度不均匀聚集体的详细尺寸和各向异性分布。** 3.具有独特光谱特性的杂多酸络合物（HC）。宽光谱多波长检测将使我们能够在HC的研究中定量化学计量，摩尔质量和结合强度。通过与UL的研究人员合作，我们将加速重要生物医学和结构生物学问题的研究，并开发用于在生理条件下研究HC的新工具。4.非理想运输模型。高浓度条件下的分析物需要修改我们UltraScan软件中的建模和优化代码。我和我的团队将开发Lamm方程的有限体积解决方案，并创建新的优化方法来覆盖此类情况。

My research focuses on the advancement of biophysical technology in the field of analytical ultracentrifugation (AUC) and related biophysical solution techniques. AUC is the method of choice for the characterization of colloidal materials. Advances in this field benefit basic research in biochemistry, physics, and material science, and provide improved characterization tools for industries like biopharma and synthetic polymer chemistry. For biopolymers and other nanomaterials, AUC offers the ability to study molecules and their assemblies under physiological conditions, where pH, ionic strength, reduction potential, temperature and other factors are easily modulated. As the new Canada 150 Research Chair for Biophysics, I have recently established the Canadian Center for Hydrodynamics, a premier laboratory equipped with three highly unique AUC instruments to accelerate biophysical research in Canada. This combination of tools is not available anywhere else, and leveraging the unique capabilities of these instruments, the goal of our proposed research is to advance previous efforts by developing new analysis protocols and software tools that will allow us to solve long-standing challenges in the following four fields:*******1. Membrane proteins (MP). MPs are biologically important molecules, but notoriously difficult to study because of their poor solubility in aqueous solvents. We will embed MPs in well-defined nanodisks containing physiological phospholipids and characterize the complexes formed. Using differential labeling with fluorophores exhibiting unique extinction profiles we hope to clearly distinguish filled from empty nanodisks and embedded MPs, their oligomerization states, and their interactions with their targets, as well as misfolded and aggregated MPs.******2. Aggregating Systems (AS). ASs are challenging to study due to their excessive heterogeneity and lack of colloidal/chemical stability. We will focus on interactions of drug candidates with amyloid- to study their influence on disrupting or dissolving harmful amyloid oligomers or inhibit their formation. We will exploit the much enhanced scanning speed and multi-speed sedimentation of the new instruments to obtain detailed size and anisotropy distributions of highly heterogeneous aggregates.******3. Hetero Complexes (HC) with unique spectral properties. Broad-spectrum multi-wavelength detection will allow us to quantify stoichiometries, molar masses and binding strengths in the study of HCs. In collaboration with investigators at UL we will accelerate research in important biomedical and structural biology problems and develop novel tools for the study of HCs under physiological conditions.******4. Modeling of non-ideal transport. Analytes under high concentration conditions require modifications in the modeling and optimization codes in our UltraScan software. My team and I will develop finite volume solutions of the Lamm equation and create new optimization methods to cover such cases.