Biomolecular Simulations as an Integral Research and Educational Tool for Molecular Systems Biology: Application to ErbB

在这个后基因组时代，系统生物学提供了一种理性和定量的方法来统一复杂的细胞相互作用，并理解决定不同细胞命运的模块化结果。然而，细胞内环境分子背景的细微差异（例如，同源蛋白、同型异构体或突变体之间磷酸化状态的差异）转化为紧急信号反应表现的关键差异，因此，在制定定量系统级模型以真正捕获不同细胞系之间的这种差异时，这是一个巨大的挑战。在ErbB家族受体介导的信号传导的背景下，分子环境塑造了细胞行使的更精细的控制，这种控制水平的定量描述一直是一个挑战。这个分子系统生物学项目是基于利用ErbB家族受体的标准和已建立的生物分子模拟（分子动力学和自由能计算），利用结构生物学最新进展提供的锚点（晶体结构），并将分子分辨率引入ErbB介导的信号传导系统生物学。该项目的预期结果是定量和预测性地描述ErbB家族受体介导的相互作用的分子结构差异如何影响早期信号事件，并通过在实验室进行的协作细胞生物学实验验证关键预测。这项工作的结果将直接补充先前在ErbB通路中建模差异信号的努力，并且人们可以期望获得对ErbB信号的分子系统生物学的综合多尺度理解。更广泛的影响-该项目有望使多尺度系统生物学和纳米生物技术的许多新应用受益。特别是，在受体激活水平上对ErbB信号的研究将为识别分子扰动触发的信号提供直接途径，这将影响我们对细胞增殖信号与高阶功能（如组织生长稳态、心脏和神经元发育）之间联系的理解。作为跨学科研究项目的补充，教育和推广项目由对工程和生物学本科生的严格和有远见的研究培训组成。为了在补充本科研究经验方面取得更广泛的影响，建立了一个三维立体环境，用于可视化生物分子结构和动画，并用于本科生和研究生水平的分子建模和模拟技术的指导。

0853539RadhakrishnanIntellectual Merit - In this post-genomic era, systems biology has provided a rational and quantitative approach to unify complex cellular interactions and comprehend modular outcomes that determine different cell fates. However, subtle differences in the molecular context of the intracellular environment (e.g., differences in phosphorylation states, between homologous proteins, isoforms, or mutants) nevertheless translate into crucial differences in the manifestations of the emergent signaling response, thereby representing a huge challenge in formulating quantitative systems-level models that truly capture such variations across distinctive cell-lines. In the context of ErbB family receptor-mediated signaling, the molecular context shapes the finer controls exercised by the cell and a quantitative description of this level of control has been a challenge. This project on molecular systems biology is based on utilizing standard and established biomolecular simulations (molecular dynamics and free energy computations) of the ErbB family receptors by leveraging the anchors (crystal structures) provided by recent progress in structural biology and introducing molecular resolution to the systems biology of ErbB-mediated signaling. The expected outcome of this project is to quantitatively and predictively describe how differences in the molecular architecture of ErbB family receptor-mediated interactions influence early signaling events and verify key predictions through collaborative cell-biology experiments performed in the laboratory. The results from this work will directly complement prior efforts in modeling differential signaling in the ErbB pathway, and together, one can expect to gain an integrated multiscale understanding of the Molecular Systems Biology of ErbB signaling. Broader Impact - This project is expected to benefit many novel applications of multiscale systems biology and nanobiotechnology. In particular, the study of ErbB signaling at the level of receptor activation will provide a direct route to discern signaling triggered by molecular perturbations which can impact our understanding of the link between cellular proliferative signals and higher order functions such as tissue-growth homeostasis, cardiac and neuronal development. Complementing the interdisciplinary research program, the educational and outreach programs are constituted by rigorous and visionary research training for undergraduate students in engineering and biology. To achieve broader impact in complementing the undergraduate research experience, a three dimensional stereo environment for visualizing biomolecular structure and animations is established and utilized for the instruction of molecular modeling and simulation techniques at the undergraduate and graduate levels.