CAREER: Computational studies of dynamic molecular search mechanisms

迄今为止，分子识别的研究主要集中在分子的结构特性，如官能团的排列。 大自然如何利用集体动态来增强特异性的例子现在正在出现，并导致从静态到动态的角度转变。 解释和合理的实验设计，以探索这些新的机制，需要相关的系统级的事件，原子级的自由能及其相关的变化。 为此目的的计算工具将被开发和应用到一个范例系统，人类蛋白O 6-烷基鸟嘌呤-DNA烷基转移酶（AGT）。 AGT通过将核苷酸翻转到其活性位点并将烷基不可逆地转移到半胱氨酸来修复修饰的鸟嘌呤和胸腺嘧啶DNA碱基。 广泛的生物化学和结构数据使其成为计算研究的理想选择。 有效地表征集体动力学自动和启动过渡路径采样模拟的手段将被引入和应用到研究的三种机制推测，使有效检测基因组中的病变：耦合不同的基板自由度之间的运动，部分核苷酸翻转动力学校对，并促进绑定导致明显的定向扫描沿着DNA。 该研究将促进用于研究生物分子系统的激活动力学的最先进方法的应用，并且将其用于处理AGT和DNA的动力学将提供对分子用于控制其相互作用的动力学策略的原子水平的洞察。计算方法将被开发并应用于AGT的研究，AGT是一种具有根本意义的蛋白质，因为它修复受损的遗传物质。 该项目将深入了解分子如何控制它们与其他分子的相互作用，这一过程是现代化学和生物学的核心。这项研究将与创建一个“动手”的计算课程，将促进跨学科的科学和通信相结合。

To date, research on molecular recognition has largely focused on structural properties of molecules such as arrangements of functional groups. Examples of how nature employs collective dynamics to enhance specificity are now emerging and leading to a shift from a static to a dynamic perspective. Interpretation and rational design of experiments to probe these novel mechanisms requires relating systems-level events to atomic-level ones and their associated changes in free energies. Computational tools for this purpose will be developed and applied to a paradigmatic system, the human protein O6-alkylguanine-DNA alkyltransferase (AGT). AGT repairs modified guanine and thymine DNA bases by flipping nucleotides into its active site and transferring alkyl groups irreversibly to cysteine. Extensive biochemical and structural data available make it ideal for computational investigations. Means for efficiently characterizing collective dynamics automatically and initiating transition path sampling simulations will be introduced and applied to the study of three mechanisms speculated to enable efficient detection of lesions in the genome: coupling of motions between different substrate degrees of freedom, partial nucleotide flipping for kinetic proofreading, and facilitated binding leading to apparent directional scanning along DNA. The research will promote application of state-of-the-art methods for studying activated dynamics to biomolecular systems, and their use to treat the dynamics of AGT and DNA will provide atomic-level insight into the kinetic strategies molecules use to control their interactions.Computational methods will be developed and applied to the study of AGT, a protein that is of fundamental interest because it repairs damaged genetic material. The project will provide insight into how molecules control their interactions with others, a process that is at the heart of much of modern chemistry and biology. This research will be coupled with creation of a "hands-on" computational curriculum that will foster interdisciplinary science and communication.