Computational Nanobiophysics: Modeling and Simulating Biomolecules in Confinement

计算纳米生物物理学：约束中生物分子的建模和模拟

• 批准号: RGPIN-2014-06091
• 负责人: deHaan, Hendrick
• 金额: $ 1.38万
• 依托单位: University of Ontario Institute of Technology
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=648811
• 关键词: Computational; Nanobiophysics; Modeling; Simulating; Biomolecules

Current fabrication technology makes it possible to design and build devices on the nanometer scale. In fact, nanofluidic devices enable the containment of single molecules such as proteins and DNA, which are only several nanometers wide. This ability has ushered in a new era of single molecule studies. Moreover, the tight confinement of the molecules in these devices can be used to influence their configuration. For example, a DNA strand in a 10 nm wide nanotube remains extended, unlike its ball-like configuration in bulk fluid. Nanofluidic devices are thus ideal for the isolation of single biomolecules allowing them to be identified, characterized, manipulated, and even modified. Given the importance of DNA and proteins in biomedical research, nanofluidic devices promise to be central in the development of next generation medical devices, diagnostics, and therapies.* In order to capitalize on these capabilities and develop applications, it is necessary to know in detail how biomolecules behave within these devices. The small length scale of the systems and short time scale of the dynamics present significant challenges for precise experimental measurements. Hence, computer simulations are an invaluable tool in probing the physics of biomolecules at the nanoscale as they can simulate the behaviour of biomolecules in nanofluidic devices at extremely high spatial and temporal resolutions even for complex systems. * Our research program uses computer simulations to study biomolecules in confinement, with a focus on three particular systems. The first system is the passage of polymers such as DNA across membranes (known as translocation) through small, constricting pores (called nanopores). This process is ubiquitous in nature as it is arises whenever DNA, RNA, or proteins cross cell membranes. It is also central to a number of emerging nanotechnolgies, the most prominent of which is the use of nanopores for rapid, inexpensive sequencing of even single strands of DNA. This technology, which is the focus of the National Human Genome Research Institute's $17M DNA sequencing project, is set to revolutionize health care by greatly facilitating personalized medicine. Our second system of study is the nanopit system. In this setup, DNA is confined in a slit between two walls, where one wall is periodically etched with pits. Since DNA prefers to occupy regions of less confinement, it tends to fill the pits. Shorter polymers, which can fit into one pit, become stuck while longer polymers continue to move through the system by hopping between pits. Applications of these dynamics include sorting DNA by length and manipulating DNA into prescribed configurations (e.g., stretched between two pits). The third system is known as CLIC (Convex Lens Induced Confinement) in which a solution of DNA strands is placed between two coverslips and a convex lens is lowered onto the top coverslip, pressing down and forming a convex upper boundary. This unique setup allows for a wide range of confinements to be observed simultaneously and thus is an ideal platform for studying the fundamental properties of DNA.* In each project, we will collaborate with experimental research groups. Through our collaborations, unique to each project, our detailed results will give insight into the experimental data which will in turn help refine the simulation approaches. Through this fundamental knowledge, we will propose and explore applications using nanofludics to identify, characterize, and manipulate biomolecules - such as sequencing DNA using nanopores. This technology will be part of the transformation of medical diagnostic, monitoring, and therapeutic approaches that are tailored to individual needs based on genetic make-up.

目前的制造技术使得在纳米尺度上设计和制造器件成为可能。事实上，纳米流体装置能够容纳蛋白质和DNA等只有几纳米宽的单分子。这种能力开创了单分子研究的新时代。此外，这些器件中分子的紧密限制可以用来影响它们的构型。例如，10 nm宽的纳米管中的DNA链保持延伸，不像其在体相流体中的球状构型。因此，纳米流体装置是分离单个生物分子的理想选择，允许它们被识别、表征、操纵甚至修改。鉴于DNA和蛋白质在生物医学研究中的重要性，纳米流体设备有望成为下一代医疗设备，诊断和治疗的核心。为了利用这些能力并开发应用程序，有必要详细了解生物分子在这些设备中的行为。小的长度尺度的系统和短的时间尺度的动态精确的实验测量提出了重大的挑战。因此，计算机模拟是探测纳米级生物分子物理学的宝贵工具，因为它们可以以极高的空间和时间分辨率模拟纳米流体设备中生物分子的行为，即使是复杂的系统。* 我们的研究计划使用计算机模拟来研究生物分子的限制，重点是三个特定的系统。第一个系统是聚合物（如DNA）通过小的收缩孔（称为纳米孔）穿过膜（称为易位）。这个过程在自然界中是普遍存在的，因为每当DNA、RNA或蛋白质穿过细胞膜时就会出现。它也是许多新兴纳米技术的核心，其中最突出的是使用纳米孔进行快速，廉价的DNA单链测序。这项技术是美国国家人类基因组研究所1700万美元DNA测序项目的重点，将通过极大地促进个性化医疗来彻底改变医疗保健。我们的第二个研究系统是纳米孔系统。在这种设置中，DNA被限制在两个壁之间的狭缝中，其中一个壁周期性地蚀刻有凹坑。由于DNA更喜欢占据限制较少的区域，因此它倾向于填充凹坑。较短的聚合物，它可以适应一个坑，成为卡住，而较长的聚合物继续通过跳坑之间的系统移动。这些动力学的应用包括按长度分选DNA和将DNA操纵成规定的构型（例如，在两个坑之间延伸）。第三种系统被称为CLIC（凸透镜诱导限制），其中DNA链的溶液被放置在两个盖玻片之间，凸透镜被降低到顶部盖玻片上，向下按压并形成凸上边界。这种独特的设置允许同时观察各种各样的限制，因此是研究DNA基本性质的理想平台。在每个项目中，我们将与实验研究小组合作。通过我们的合作，每个项目都是独一无二的，我们的详细结果将深入了解实验数据，这反过来又有助于改进模拟方法。通过这些基础知识，我们将提出并探索使用纳米流体来识别，表征和操纵生物分子的应用-例如使用纳米孔对DNA进行测序。这项技术将成为医学诊断、监测和治疗方法转型的一部分，这些方法将根据基因组成量身定制，以满足个人需求。