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The mechanism of formamide hydrolysis in water from ab initio calculations and simulations

机译：从头计算和模拟从水中甲酰胺水解的机理

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摘要

The neutral hydrolysis of formamide in water is a suitable reference to quantify the efficiency of proteolytic enzymes. However, experimental data for this reaction has only very recently been obtained and the kinetic constant determined experimentally is significantly higher than that predicted by previous theoretical estimations. In this work, we have investigated in detail the possible mechanisms of this reaction. Several solvent models have been considered that represent a considerable improvement on those used in previous studies. Density functional and ab initio calculations have been carried out on a system which explicitly includes the first solvation shell of the formamide molecule. Its interaction with the bulk has been treated with the aid of a dielectric continuum model. Molecular dynamics simulations at the combined density functional/molecular mechanics level have been carried out in parallel to better understand the structure of the reaction intermediates in aqueous solution. Overall, the most favored mechanism predicted by our study involves two reaction steps. In the first step, the carbonyl group of the formamide molecule is hydrated to form a diol intermediate. ne corresponding transition structure involves two water molecules. From this intermediate, a water-assisted proton transfer occurs from one of the hydroxy groups to the amino group. This reaction step may lead either to the formation of a new reaction intermediate with a marked zwitterionic character or to dissociation of the system into ammonia and formic acid. The zwitterionic intermediate dissociates quite easily but its lifetime is not negligible and it could play a role in the hydrolysis of substituted amides or peptides. The predicted pseudo-first-order kinetic constant for the rate-limiting step (the first step) of the hydrolysis reaction at 25 degrees C (3.9 x 10(-10)s(-1)) is in excellent agreement with experimental data (1.1 x 10-(10) s(-1)).
机译：甲酰胺在水中的中性水解是量化蛋白水解酶效率的合适参考。然而，该反应的实验数据只是最近才获得的，并且实验确定的动力学常数明显高于以前的理论估计所预测的动力学常数。在这项工作中，我们详细研究了该反应的可能机理。已经考虑了几种溶剂模型，它们代表了以前研究中使用的那些模型的显着改进。已经在明确包括甲酰胺分子的第一溶剂化壳的系统上进行了密度泛函和从头算。借助介电连续体模型处理了其与主体之间的相互作用。为了更好地理解水溶液中反应中间体的结构，并行进行了密度函数/分子力学相结合的分子动力学模拟。总体而言，我们的研究预测的最有利机制涉及两个反应步骤。在第一步中，将甲酰胺分子的羰基水合以形成二醇中间体。相应的过渡结构涉及两个水分子。从该中间体发生水助质子从羟基之一转移到氨基。该反应步骤可能导致形成具有明显两性离子特性的新反应中间体，或者导致系统分解为氨和甲酸。两性离子中间体很容易解离，但其寿命不可忽略，并且可以在取代酰胺或肽的水解中发挥作用。在25摄氏度（3.9 x 10（-10）s（-1））下水解反应的限速步骤（第一步）的预测拟一级动力学常数与实验数据（ 1.1 x 10-（10）s（-1））。

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