From compatible solutes to ribozymes at HHP conditions

该子项目的关键思想是使用从头开始模拟及其 QM/MM 扩展来预测性探索生物分子相关性小溶质和功能生物分子在千巴压力下的动态景观。在过去的资助期间，我们在模拟和新颖分析工具的层面上建立了机制，这使我们能够定量计算和分配小分子溶质的红外光谱，例如TMAO(aq)，从中红外到千巴压力下的远红外(THz)频率范围。这些技术现在将用于系统地研究更复杂的溶质，例如氨基酸和模型肽，以定量了解振动光谱探针方面亲水性和疏水性基团的压力响应。基于高压下 TMAO(aq) 解决方案取得的进展，完整的从头计算模拟将为蛋白质模拟高压力场的合理设计做出重要的协作贡献。 最后，在第一轮资助期间对发夹核酶反应位点的构象压力响应有了初步了解后，现在的重点将转向使用 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.