Snapshots of the Reading and Writing of Synthetic Genetic Polymers

合成遗传学旨在将核酸扩展为新的非天然遗传聚合物，称为异种核酸(XNA)，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展。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”。尽管这种XNA酶的开发取得了进展，但仍然存在重大挑战，因为迄今进化出的异种底物酶的效率和保真度通常低于天然酶。对这些进程的结构性洞察将提供非常有价值的见解，有助于取得重要进展。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，我们将在过去成功结构阐明DNA聚合酶与合成底物相互作用的基础上再接再厉。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，以获得非常有效的XNA酶。通过与该领域两位世界知名的主要参与者合作，该项目将获得巨大的动力：菲利普·霍利格(英国剑桥MRC)将提供XNA酶的独特专业知识，Piet Herdewijn(比利时KU鲁汶)将提供XNA组分的化学合成方面的独特专业知识。这一阵容将提供一个独特的环境，推动这一项目的进展，该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.