Sequencing a DNA molecule using a Synthetic Nanopore

描述(申请人提供)：我们计划探索使用一种革命性的硅集成电路对DNA分子进行测序的可行性，这种集成电路将纳米孔机制与分子陷阱结合在一起。基本组件是由金属氧化物半导体(MOS)电容器形成的坚固的纳米厚薄膜中的一个纳米直径的孔。为了对分子进行排序，当DNA通过孔转移时，使用电容器上的电极测量与每个碱基相关的偶极矩所产生的电压。1纳米直径的孔是一个关键的规格，因为它迫使与每个底座相关的唯一偶极矩在移位过程中几乎横向于电极，同时最大限度地减少热波动并排除大部分水。另一个关键的规格是隔开形成电容器的电极的二氧化硅绝缘体的厚度。测序的空间分辨率基本上是由二氧化硅厚度决定的。直径1 nm的孔和0.7 nm厚的氧化物，我们希望能够在移位过程中测量与跨越绝缘子的单个碱基相关的电信号。为了便于信号恢复，我们打算在分子通过孔道的移位过程中捕获分子，迫使它在电极之间来回振荡。DNA位置的振荡允许使用窄带同步检测(锁定技术)来提高电信噪比水平，而不会影响吞吐量，并有效地平均与DNA构象变化和离子分布相关的噪声。虽然我们计划制造和测试一种集成了纳米孔-电容机制和分子陷阱的集成电路，并对其进行优化，以对单个DNA分子进行测序，但同时我们也计划使用分子动力学与自洽的3D泊松解算器相结合来模拟该机制的性能并测试其理论分辨率。

DESCRIPTION (provided by applicant): We plan to explore the feasibility of sequencing a DNA molecule using a revolutionary type of silicon integrated circuit that incorporates a nanopore mechanism with a molecular trap. The essential component is a single, nanometer-diameter pore in a robust, nanometer-thick membrane formed from a Metal Oxide Semiconductor (MOS) capacitor. To sequence the molecule, the voltage induced by the dipole moment associated with each base is measured using the electrodes on the capacitor as the DNA translocates through the pore. The 1 nm diameter of the pore is a key specification since it forces the unique dipole moment associated with each base to be nearly transverse to electrodes during a translocation, while minimizing thermal fluctuations and excluding most of the water. Another crucial specification is the thickness of the SiO2 insulator separating the electrodes forming the capacitor. The spatial resolution for sequencing is essentially determined by the SiO2 thickness. With a 1 nm diameter pore and a 0.7nm thick oxide, we expect to be able to measure the electrical signal associated with a single base spanning the insulator during a translocation. To facilitate signal recovery, we intend to trap the molecule during the translocation through the pore, forcing it to oscillate back-and-forth between the electrodes. The oscillation in the position of the DNA allows for narrow-band synchronous detection (lock-in techniques) to be used to improve the electrical signal-to-noise level without compromising the throughput and effectively averages out the noise associated with conformational changes in the DNA and the ion distribution. While we plan to fabricate and test an integrated circuit incorporating a nanopore-capacitor mechanism with a molecular trap and optimize it for sequencing a single molecule of DNA, at the same time we also plan to simulate the performance and test the theoretical resolution of the mechanism using molecular dynamics in conjunction with a self-consistent 3D Poisson solver.