Snapshots of the Reading and Writing of Synthetic Genetic Polymers

合成遗传学旨在将核酸扩展到称为“异种核酸（XNA）”的新的非天然遗传聚合物，以促进长期数据存储，生物技术，诊断和医学等许多领域的进步。基于XNA的应用的关键是用于XNA记录（XNA聚合酶）和阅读（XNA逆转录酶）的酶“机器”。尽管在开发此类XNA酶方面取得了进展，但主要挑战仍然存在，因为迄今为止进化的酶与异种底物的效率和保真度通常低于天然对应物。对这些过程的结构性见解将提供非常有价值的见解，从而导致重要的进展。然而，缺乏重要的结构。因此，本项目的目的是首次阐明XNA的酶记录和阅读的结构基础。因此，我们将建立在我们过去的成功，在DNA聚合酶与合成底物的相互作用的结构阐明。这些结构将为遗传交易的化学边界条件提供新的见解，并将指导进一步的工程设计，以获得非常有效的XNA酶。通过与该领域的两个世界知名的主要参与者合作，该项目将获得重大动力：Philipp Holliger（MRC剑桥，英国）将提供XNA酶的独特专业知识，Piet Herdewijn（KU Leuven，比利时）将提供XNA组分的化学合成。这一阵容将提供一个独特的环境，促进这个项目的进展，这个项目位于一个世界范围内高度可见和竞争激烈的领域。

Synthetic genetics aims to expand nucleic acids to new non-natural genetic polymers called ‘xeno nucleic acids (XNA)’ to foster advances in many areas like long-term data storage, biotechnology, diagnostics and medicine. Key for XNA-based applications are enzymatic “machines” for XNA recording (XNA polymerases) and reading (XNA reverse transcriptases). Despite progress in the development of such XNA enzymes, major challenges remain since efficiency and fidelity of the hitherto evolved enzymes with xeno substrates is generally lower than with the natural counterparts. Structural insights into these processes would provide highly valuable insights leading to important advances. However, important structures are lacking. Thus, the aim of this project is the first time elucidation of the structural basis for enzymatic recording and reading of XNA. Thereby we will build on our past success in the structural elucidation of the interplay of DNA polymerases with synthetic substrates. These structures will provide new insights into the chemical boundary conditions of genetic transactions and will guide for further engineering with the goal to obtain very efficient XNA enzymes. Significant momentum for this project will be gained by collaborating with with two world-wide known major protagonists in the field: Philipp Holliger (MRC Cambridge, UK) will provide unique expertise in XNA enzymes and Piet Herdewijn (KU Leuven, Belgium) in the chemical synthesis of XNA components. This line-up will provide a unique setting spurring the progress in this project that lies in a world-wide highly visible and competitive field.