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Abstract：
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.
摘要：
NMR（核磁共振）光谱可以对生物大分子的结构和动力学进行重要的原子观察；但是，实验光谱的可靠分配通常很困难。在这里，量子力学/分子力学(QM/MM)计算可以提供至关重要的支持。模拟的一个主要问题是实验NMR信号在更长的时间尺度上是时间平均的，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，具有代表性的结构集合的足够大的平均值是必不可少的。这需要对可靠模拟的高计算要求。对于生物系统中的NMR测量，一个主要感兴趣的原子核是31P，因为它都是高度存在的(例如，在核酸中)且易于观察。我们本研究的重点是开发一个强大且具有计算成本效益的框架，用于模拟核苷酸的31PNMR化学位移。我们应用该方案研究了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，其次是QM/MM结构优化和NMR计算。总的来说,我们的研究是蛋白质环境中最全面的基于QM的31P研究之一，并且是第一个提供蛋白质环境中多个核苷酸状态的计算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测过程，旨在弥合测量和计算的NMR光谱特性之间的差距。
