Oligomerization, confinement and the folding barrier

描述(申请人提供)：由于模拟和实验的限制，对蛋白质折叠的最终理解可能来自于通过实验广泛验证和测试的详细模拟的耦合方法。然而，由于所涉及的时间尺度较长，以及详细的原子模型的困难和复杂性，开发能够定量地与实验动力学联系起来的模拟方法仍然是一个巨大的理论挑战。最后，随着模拟能够定量预测蛋白质在溶液中折叠的实验动力学，新的挑战出现了：理解生物相关环境中的折叠，例如天然非结构蛋白质和受限空间中的折叠。在这里，我们提出了新的第二代分布式计算方法来解决这些挑战，并将这些方法应用于与蛋白质如何在溶液中自组装相关的问题，以及在天然非结构蛋白质和蛋白质在受限空间中折叠的生物相关环境中，作为重要生物环境的模型，如核糖体、伴侣和细胞质。虽然蛋白质折叠本身已经被计算研究了很多年，但我们的工作与其他方法的不同之处在于：(1)使用新的分布式计算方法，使用详细的、完全原子化的、显式的溶剂模型来模拟长时间尺度的动力学；(2)应用这些详细的模型来解决天然非结构蛋白质的生物学背景下的折叠问题和限制。与实验的定量比较对于我们的计算方法的测试和更大的影响都是至关重要的，这种实验合作是通过一系列合作提出的。最后，拟议的工作应该会对我们对几种与蛋白质相关的疾病的基本理解产生影响，例如涉及P53四聚化和激活域突变的癌症。此外，通过了解有限空间中折叠的性质，1将深入了解体内蛋白质折叠的性质，这将是我们理解蛋白质折叠及其与生物学和生物医学问题的联系的重要下一步。

DESCRIPTION (provided by applicant): Due to the limitations of both simulation and experiment, an ultimate understanding of protein folding will likely come from a coupled approach of detailed simulations extensively validated and tested by experiment. However, developing simulation methodology which can quantitatively connect with experimental kinetics still remains a great theoretical challenge, due to the long timescales involved and the difficulties and complexities of detailed, atomistic models. Finally, with the ability of simulation to quantitatively predict experimental kinetics for protein folding in solution, new challenges emerge: understanding folding in biologically relevant contexts, such as natively unstructured proteins and folding in confined spaces. Here, we propose new, second generation distributed computing methods to tackle these challenges and the application of these methods to questions related to how proteins self-assemble in solution, as well as in the biologically relevant contexts of natively unstructured proteins and proteins folding in confined spaces as a model for important biological contexts, such as ribosomes, chaperones, and the cytosol. While protein folding has itself been studied computationally for many years, our work differs from other approaches in (1) its use of novel distributed computing methods for simulating long time scale kinetics using detailed, fully atomistic, explicit solvent models and (2) the application of these detailed models to address questions of folding in the biological contexts of natively unstructured proteins and confinement. A quantitative comparison to experiment is critical for both the testing and greater impact of our computational methods and such experimental collaborations are proposed via a series of collaborations. Finally, the proposed work should have an impact on our basic understanding of several protein- related diseases, such as cancers involved in mutations of the tetramerization and activation domains of p53. Also, by understanding the nature of folding in confined spaces, 1 would gain insight into the nature of protein folding in vivo, which would be an important next step in our understanding of protein folding and its connection to biology and biomedical questions.