Systematic QM/MM Study for Predicting 31P NMR Chemical Shifts of Adenosine Nucleotides in Solution and Stages of ATP Hydrolysis in a Protein Environment,Journal of Chemical Theory and Computation

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Systematic QM/MM Study for Predicting 31P NMR Chemical Shifts of Adenosine Nucleotides in Solution and Stages of ATP Hydrolysis in a Protein Environment
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2024-03-18 , DOI: 10.1021/acs.jctc.3c01280
Judit Katalin Szántó ₁ , Johannes C B Dietschreit _{1,

2} , Mikhail Shein ₃ , Anne K Schütz ₃ , Christian Ochsenfeld _{1,

4}

Affiliation

NMR (nuclear magnetic resonance) spectroscopy allows for important atomistic insights into the structure and dynamics of biological macromolecules; however, reliable assignments of experimental spectra are often difficult. Herein, quantum mechanical/molecular mechanical (QM/MM) calculations can provide crucial support. A major problem for the simulations is that experimental NMR signals are time-averaged over much longer time scales, and since computed chemical shifts are highly sensitive to local changes in the electronic and structural environment, sufficiently large averages over representative structural ensembles are essential. This entails high computational demands for reliable simulations. For NMR measurements in biological systems, a nucleus of major interest is ³¹P since it is both highly present (e.g., in nucleic acids) and easily observable. The focus of our present study is to develop a robust and computationally cost-efficient framework for simulating ³¹P NMR chemical shifts of nucleotides. We apply this scheme to study the different stages of the ATP hydrolysis reaction catalyzed by p97. Our methodology is based on MM molecular dynamics (MM-MD) sampling, followed by QM/MM structure optimizations and NMR calculations. Overall, our study is one of the most comprehensive QM-based ³¹P studies in a protein environment and the first to provide computed NMR chemical shifts for multiple nucleotide states in a protein environment. This study sheds light on a process that is challenging to probe experimentally and aims to bridge the gap between measured and calculated NMR spectroscopic properties.

中文翻译：

用于预测溶液中腺苷核苷酸的 31P NMR 化学位移和蛋白质环境中 ATP 水解阶段的系统 QM/MM 研究

NMR（核磁共振）光谱可以从原子角度深入了解生物大分子的结构和动力学；然而，可靠的实验光谱分配通常很困难。在此，量子力学/分子力学（QM/MM）计算可以提供关键的支持。模拟的一个主要问题是实验核磁共振信号是在更长的时间尺度上进行时间平均的，并且由于计算的化学位移对电子和结构环境的局部变化高度敏感，因此在代表性结构系综上足够大的平均值是至关重要的。这对可靠模拟提出了很高的计算要求。对于生物系统中的 NMR 测量，主要感兴趣的核是³¹ P，因为它的存在率很高（例如，在核酸中）并且易于观察。我们目前研究的重点是开发一个强大且计算成本高效的框架来模拟核苷酸的³¹ P NMR 化学位移。我们应用该方案来研究 p97 催化的 ATP 水解反应的不同阶段。我们的方法基于 MM 分子动力学 (MM-MD) 采样，然后进行 QM/MM 结构优化和 NMR 计算。总体而言，我们的研究是蛋白质环境中最全面的基于 QM 的³¹ P 研究之一，也是第一个为蛋白质环境中的多个核苷酸状态提供计算 NMR 化学位移的研究。这项研究揭示了一个具有挑战性的实验探索过程，旨在弥合测量和计算的核磁共振波谱特性之间的差距。

更新日期：2024-03-18

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