Theory and computation of the structural and dynamic origins of protein misfolding and biomolecular electromagnetic sensing

随着预期寿命的增加，我们面临着目前无法治愈的疾病日益流行的问题，这些疾病严重影响着老年人口。其中最常见的是癌症;另一种是蛋白质错误折叠疾病，包括阿尔茨海默病。在我们研究计划的一个组成部分中，我们建议通过对这些病理发生时起作用的分子机制的基本了解，寻找新的疗法来诊断甚至预防这些疾病。这样的理解涉及量化生物分子的能量、熵和结构。通过一套计算和理论的技术，我们将阐明微妙的分子运动，流氓蛋白质进行时，他们错误折叠。令人惊讶的是，一条共同的线索可能将癌症与蛋白质错误折叠疾病联系起来。癌细胞是一个匆忙的细胞，这导致蛋白质质量控制的损失。癌细胞表面的蛋白质可能会错误折叠。通过计算识别这些错误折叠可能使我们能够产生药物或抗体，这些药物或抗体可以选择性地与癌细胞上的蛋白质结合，而不是与健康细胞结合，这是癌症治疗的最终目标。这种蛋白质的错误折叠是导致卢伽雷病的原因，它通常起着分子抗氧化剂的作用。在分子功能的进化史中，有一个不寻常的情节转折，另一种蛋白质可能利用其抗氧化行为来实际测量地球磁场的方向。这种被称为隐花色素的蛋白质是如何做到这一点的，这甚至更奇怪，涉及到一种量子力学机制，在这种机制中，电子的自旋像地球磁场中的陀螺一样进动。电子通常成对并隐藏起来，但蓝光的闪光可以将一对电子分开，使它们变得可见。电子是重组还是永远分离，取决于蛋白质在地球磁场中的方向，因此蛋白质可以被鸟类和其他动物用作一种化学指南针来导航。导致这种行为的自旋相关反应目前是一个谜;我们将使用量子计算化学的新分析方法和工具来研究它们，以揭示生物学如何“理解”和利用量子力学。

As life expectancy increases, we face an increasing prevalence of presently incurable diseases that severely affect the older population. One of the most common of these is cancer; another is protein misfolding disease, including Alzheimer's disease. In one component of our research program, we propose to find new therapies to diagnose or even prevent these diseases, through a fundamental understanding of the molecular mechanisms at work when these pathologies occur. Such an understanding involves quantifying energy, entropy, and structure for biomolecules. Through a suite of computational and theoretical techniques, we will elucidate the subtle molecular motions that rogue proteins undertake when they misfold. Surprisingly, a common thread may connect cancer to protein misfolding diseases. A cancer cell is a cell in a hurry, which results in a loss of protein quality control. Proteins on the surface of cancer cells may likely be misfolded. Identifying these misfolds computationally may allow us to generate drugs or antibodies that can bind selectively to proteins on cancer cells and not to healthy cells, the ultimate goal of cancer therapy. The protein whose misfolding is responsible for Lou Gehrig's disease normally functions as a molecular anti-oxidant. In an unusual plot-twist in the evolutionary story of molecular function, another protein may use its anti-oxidant behavior to actually measure the direction of the earth's magnetic field. How this protein, called cryptochrome, does this is even more bizarre, involving a quantum-mechanical mechanism where the spins of electrons precess like a top in the earth's field. Electrons are normally paired up and hidden, but a flash of blue light can separate a pair of electrons so that they become visible. Whether or not the electrons recombine or drift apart forever depends on the orientation of the protein in the earth's field, so the protein can be used as a kind of chemical compass by birds and other animals to navigate. The spin-dependent reactions that give rise to such behavior are currently a mystery; we will investigate them using new analytical approaches and tools from quantum computational chemistry, to uncover how biology may "understand" and exploit quantum mechanics.