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速离心法(AUC)和相关生物物理溶液技术方面的进展。AUC是表征胶体材料的首选方法。该领域的进展有利于生物化学、物理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，在生理条件下，pH、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水动力学中心，这是一个配备了三台非常独特的AUC仪器的顶级实验室，以加速加拿大的生物物理研究。这种工具的组合在其他任何地方都是不可用的，利用这些仪器的独特能力，我们拟议的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)。MPS是生物学上重要的分子，但众所周知，由于它们在水溶液中的溶解性很差，所以很难研究。我们将MPS嵌入到包含生理磷脂的定义明确的纳米盘中，并对形成的络合物进行表征。利用显示独特消光轮廓的荧光团的差异标记，我们希望清楚地区分填充的纳米盘和嵌入的MP，它们的齐聚状态，它们与目标的相互作用，以及错误折叠和聚集的MP。*2.聚集系统(AS)由于其高度的异质性和缺乏胶体/化学稳定性，ASS的研究具有挑战性。我们将重点研究候选药物与淀粉样蛋白的相互作用，以研究它们对破坏或溶解有害的淀粉样寡聚体或抑制其形成的影响。我们将利用新仪器大大提高的扫描速度和多速度沉积来获得高度非均质聚集体的详细尺寸和各向异性分布。*3.具有独特光谱性质的杂化络合物(HC)。广谱多波长检测将使我们能够在HCS的研究中量化化学计量、摩尔质量和结合强度。与UL的研究人员合作，我们将加快重要生物医学和结构生物学问题的研究，并开发生理条件下HCS研究的新工具。*4.非理想运输的建模。高浓度条件下的分析物需要修改我们的超声软件中的建模和优化代码。我和我的团队将开发拉姆方程的有限体积解，并创建新的优化方法来涵盖这些情况。

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.