From compatible solutes to ribozymes at HHP conditions

本子项目的关键思想是使用从头算模拟及其QM/MM扩展来预测在千巴压力下生物分子相关的小溶质和功能生物分子的动态景观。在过去的资助期间，我们建立了机器，无论是在模拟水平还是在新的分析工具水平，这使我们能够定量计算和分配小分子溶质（如TMAO(aq)）的红外光谱，从中红外到远红外（太赫兹）频率范围在千巴压力下。这些技术现在将被应用于系统地研究更复杂的溶质，如氨基酸和模型肽，以定量地了解在振动光谱探针方面亲水和疏水基团的压力响应。基于高压下TMAO（aq）解的研究进展，全从头算模拟将为蛋白质模拟高压力场的合理设计做出重要贡献。最后，在第一个资助期获得了对发夹核酶反应位点的构象压力响应的首次见解之后，现在的重点将转向利用QM/MM分子动力学模拟来阐明酶促步骤本身的压力响应，即自裂解反应。

The key idea underlying this subproject is to use ab initio simulation and its QM/MM extension to predictively explore the dynamical landscape of both small solutes of biomolecular relevance and of functional biomolecules at pressures in the kilobar regime. In the past funding period, we established the machinery, both at the level of simulation and at the level of novel analysis tools, which allows us to quantitatively compute and to assign infrared spectra of small molecular solutes such as TMAO(aq) from the mid-infrared down to the far-IR (THz) frequency range at kilobar pressures. These techniques will now be applied to study systematically more complex solutes such as amino acids and model peptides in an effort to quantitatively understand the pressure-response of hydrophilic and hydrophobic groups in terms of vibrational spectroscopy probes. Based on advances made for TMAO(aq) solutions at high pressures, full ab initio simulations will be an important collaborative contribution toward the rational design of high-pressure force fields for protein simulations. Finally, having obtained first insights into the conformational pressure-response of the reactive site of hairpin ribozyme in the first funding period, the thrust will now shift toward elucidating the pressure-response of the enzymatic step itself, which is the self-cleavage reaction, using QM/MM molecular dynamics simulations.