Benayad Zakarya, Bova Saint-André Matthias, Stirnemann Guillaume
CNRS Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, PSL University, Université de Paris, 13 rue Pierre et Marie Curie, 75005Paris, France.
J Phys Chem B. 2022 Oct 20;126(41):8251-8265. doi: 10.1021/acs.jpcb.2c04259. Epub 2022 Oct 6.
Phosphate groups are ubiquitous in biomolecules and are usually incorporated through phosphoester bonds between alcohol groups and orthophosphate. The formation of this bond is exceptionally difficult, with associated barriers of 30-45 kcal/mol in the absence of catalysts. In abiotic conditions, polymerizing nucleic acids without enzymes remains very challenging and is still a partly unsolved problem that severely questions the RNA World hypothesis for the origins of life. Offering a solution to this problem would involve a detailed knowledge of the reaction energetics and mechanisms, yet these remain not fully understood at a molecular level, especially because of the very slow reaction rates that represent a significant challenge for the experiments. The number of involved reaction coordinates and the possible role of the solvent in assisting the reaction are challenging for computational studies. Here, we use extensive ab initio molecular dynamics simulations using semiempirical tight-binding methods and enhanced sampling to address these issues. We first show that the choice of the tight-binding method is greatly limited by the instability of the water liquid phase for most DFTB generations and parameter sets that are widely available. We then focus on a model reaction involving methanol and orthophosphate, for which the two protonation states (mono- and dianionic) that are dominant around neutral pH are considered. We compare different proton coordinates that enable (or not) the participation of solvent water molecules. Our simulations suggest that in all cases, a dissociative associative mechanism, with an intermediate metaphosphate, is favored. The main difference between the two phosphate species is that reaction with the monoanion is assisted by the substrate, while that with the dianion involves solvent water molecules. Our results are in agreement with early experimental measurements, but the reaction barriers are underestimated in our framework. We believe that our approach provides an interesting perspective on how to sample the reaction phase space efficiently, but it calls for future studies using more accurate descriptions of chemical reactivity.
磷酸基团在生物分子中普遍存在，通常通过醇基与正磷酸盐之间的磷酸酯键结合。这种键的形成异常困难，在没有催化剂的情况下，相关能垒为30 - 45千卡/摩尔。在非生物条件下，无酶聚合核酸仍然极具挑战性，并且仍然是一个部分未解决的问题，这严重质疑了生命起源的RNA世界假说。解决这个问题需要详细了解反应能量学和机制，但在分子水平上这些仍未完全理解，特别是因为非常缓慢的反应速率对实验构成了重大挑战。涉及的反应坐标数量以及溶剂在协助反应中可能发挥的作用对计算研究来说具有挑战性。在这里，我们使用基于半经验紧束缚方法的广泛从头算分子动力学模拟和增强采样来解决这些问题。我们首先表明，对于大多数广泛可用的DFTB代和参数集，由于水液相的不稳定性，紧束缚方法的选择受到极大限制。然后我们专注于一个涉及甲醇和正磷酸盐的模型反应，考虑了在中性pH附近占主导的两种质子化状态（单阴离子和双阴离子）。我们比较了不同的质子坐标，这些坐标能够（或不能）使溶剂水分子参与反应。我们的模拟表明，在所有情况下，一种具有中间偏磷酸盐的离解缔合机制是有利的。两种磷酸盐物种之间的主要区别在于，与单阴离子的反应由底物协助，而与双阴离子反应则涉及溶剂水分子。我们的结果与早期实验测量结果一致，但在我们的框架中反应能垒被低估了。我们相信我们的方法为如何有效地采样反应相空间提供了一个有趣的视角，但它需要未来使用更准确的化学反应描述进行研究。
