CAREER: Structure, Dynamics, and Energetics of DNA Mismatch Recognition

这位研究者有兴趣帮助扩大结构生物学的研究，不仅解决水环境中的单分子，而且解决异质环境中的大分子复合物。他通过计算机模拟建模来接近这个领域。在这个项目中，他选择了错配修复复合物和DNA之间相互作用的原子细节作为他的重点。他将利用细菌和真核生物复合体的数据进行调查。他将回答三个关键问题：1)MutS蛋白如何区分有缺陷的DNA和正常的DNA？2)。缺陷DNA的结合如何导致修复启动？3)。MutHLS系统真核同系物中不同类型DNA缺陷特化的分子起源是什么？为了建模，将使用最近开发的基于广义Born形式的隐式溶剂方法，并在蛋白质- dna相互作用的背景下进一步发展，以平衡计算效率和溶剂环境的现实描述。该项目的第二个主要组成部分是引入计算机模拟建模，作为面向生物学学生的结构生物学课程的一部分。对生物环境的隐式描述对教育特别有吸引力，因为这种模型极大地简化和加速了原子级建模。此外，PI将致力于简化高级分子建模和分析任务的界面，从而使生物学学生专注于技术在生物学问题上的应用，而不是有时压倒性的模拟方法的技术细节。细胞通常能有效地修复遗传物质中的错误。然而，当错误得不到修复时，由此产生的缺陷会导致细胞代谢的严重问题。显然，修复机制对所有生物体都至关重要。一种特定修复机制的功能将作为本尝试的主题，通过计算机模拟改进结构生物学建模，并通过专业课程和计算机用户界面使这种建模更容易为生物学学生所接受。

This investigator is interested in helping to broaden structural biology studies to address not only single molecules in aqueous environments but also large molecular complexes in heterogeneous environments. He approaches this area through modeling via computer simulations. For this project he has chosen as his focus the atomic details of the interactions between mismatch repair complexes and DNA. He will carry out his investigations with data from both the bacterial and eukaryotic complexes. He will address three key questions: 1.) How does the MutS protein differentiate defective DNA from regular DNA? 2.) How does binding of defective DNA lead to repair initiation? 3.) What is the molecular origin of specialization for different types of DNA defects in eukaryotic homologs of the MutHLS system? For the modeling, recently developed implicit solvent methods based on the generalized Born formalism will be used and developed further in the context of protein-DNA interactions in order to balance computational efficiency with a realistic description of the solvent environment. A second major component of this project is the introduction of computer simulation modeling as part of structural biology curricula directed at biology students. Implicit descriptions of biological environments are particularly attractive for education because such models greatly simplify and accelerate atomic-level modeling. In addition, the PI will work on simplifying interfaces for advanced molecular modeling and analysis tasks, thus allowing biology students to focus on applications of the techniques to biological questions rather than on the sometimes overwhelming technical details of the simulation methodologies. Cells normally repair errors in genetic material efficiently. When errors are not repaired, however, the resulting defects can cause profound problems in cellular metabolism. Obviously, repair mechanisms are of utmost importance to all organisms. The functioning of one specific repair mechanism will serve as the subject of this attempt to improve structural biological modeling via computer simulation and to make such modeling more accessible to biology students through specialized courses and computer-user interfaces.