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，细胞内环境分子环境的细微差异(例如，磷酸化状态的差异，同源蛋白、异构体或突变体之间的差异)仍然转化为紧急信号响应表现的关键差异，因此在建立真正捕捉不同细胞系之间这种差异的定量系统水平模型方面存在巨大的挑战。在ErbB家族受体介导的信号传递的背景下，分子背景塑造了细胞行使的更精细的控制，而对这种控制水平的定量描述一直是一个挑战。这个关于分子系统生物学的项目是基于利用标准的和已建立的ErbB家族受体的生物分子模拟(分子动力学和自由能计算)，利用结构生物学的最新进展提供的锚(晶体结构)，并将分子解析引入ErbB介导的信号传递的系统生物学。该项目的预期结果是定量和预测地描述ErbB家族受体介导的相互作用的分子结构的差异如何影响早期信号事件，并通过在实验室进行的细胞生物学合作实验来验证关键预测。这项工作的结果将直接补充先前在ErbB途径中建立差异信号模型的努力，并有望对ErbB信号的分子系统生物学有一个完整的多尺度理解。更广泛的影响--该项目预计将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由分子扰动触发的信号提供直接途径，分子扰动可能影响我们对细胞增殖信号与更高阶功能之间的联系的理解，如组织生长稳态、心脏和神经元发育。作为跨学科研究计划的补充，教育和推广计划是由对工程和生物本科生进行严格和有远见的研究培训组成的。为了在补充本科生研究经验方面取得更广泛的影响，建立了一个可视化生物分子结构和动画的三维立体环境，并将其用于本科生和研究生水平的分子建模和模拟技术的教学。

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.