当前的MD力场未能捕获蛋白质结构和波动的关键特征：亲环素A和T4溶菌酶的案例研究
Current MD forcefields fail to capture key features of protein structure and fluctuations: A case study of cyclophilin A and T4 lysozyme
摘要：
球状蛋白质在溶液中经历热波动，同时保持整体明确的折叠结构。特别是，研究表明，球状蛋白质的核心结构在通过X射线晶体学与基于溶液的NMR光谱学解决时存在微小但重要的差异。鉴于这些差异，目前还不清楚分子动力学（MD）模拟是否可以准确地概括蛋白质构象。因此，我们进行了广泛的MD模拟在多个力场和采样技术，以调查计算机模拟可以捕捉实验中观察到的构象合奏的程度。通过分析原子坐标和核心包装的波动，我们表明，在MD模拟中采样的构象都远离和采样一个更大的构象空间比在NMR实验中观察到的结构的合奏。然而，我们发现，添加与通过核Overhauser效应测量获得的残基间距离限制相匹配的残基间距离限制，使MD模拟能够采样更多类似NMR的构象，尽管限制MD和NMR系综中的核心堆积特征之间仍然存在显着差异。考虑到从MD模拟获得的蛋白质结构具有较小的和较低密度的蛋白质核心相比，通过NMR解决，我们建议，未来的改进MD力场的目标应该是增加蛋白质核心中的疏水残基的包装。
英文摘要：
Globular proteins undergo thermal fluctuations in solution, while maintaining an overall well-defined folded structure. In particular, studies have shown that the core structure of globular proteins differs in small, but significant ways when they are solved by x-ray crystallography versus solution-based NMR spectroscopy. Given these discrepancies, it is unclear whether molecular dynamics (MD) simulations can accurately recapitulate protein conformations. We therefore perform extensive MD simulations across multiple force fields and sampling techniques to investigate the degree to which computer simulations can capture the ensemble of conformations observed in experiments. By analyzing fluctuations in the atomic coordinates and core packing, we show that conformations sampled in MD simulations both move away from and sample a larger conformational space than the ensemble of structures observed in NMR experiments. However, we find that adding inter-residue distance restraints that match those obtained via Nuclear Overhauser Effect measurements enables the MD simulations to sample more NMR-like conformations, though significant differences between the core packing features in restrained MD and the NMR ensemble remain. Given that the protein structures obtained from the MD simulations possess smaller and less dense protein cores compared to those solved by NMR, we suggest that future improvements to MD forcefields should aim to increase the packing of hydrophobic residues in protein cores.
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