最小集体变量的构象转变在操纵和温度加速MD模拟:一个T4溶菌酶的案例研究。

IF 2.9 2区 化学 Q3 CHEMISTRY, PHYSICAL
The Journal of Physical Chemistry B Pub Date : 2025-05-29 Epub Date: 2025-05-15 DOI:10.1021/acs.jpcb.5c01129
Salsabil Abou-Hatab, Cameron F Abrams
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引用次数: 0

摘要

蛋白质的构象转变很难用平衡分子动力学来观察,并且在无法获得高分辨率结构数据的情况下,像靶向MD这样的增强采样方法具有挑战性。低分辨率的数据,如原子间距离和角度,可以作为偏置导向MD (SMD)模拟的集体变量(cv),但cv的最佳选择和数量尚不清楚。在这里,我们确定了一组最小的CVs,驱动T4溶菌酶在亚稳态之间的成功转变。我们使用温度加速MD (TAMD)来验证它们在没有目标偏差的情况下加速构象变化。我们发现,在最大和最小的尺度上,CVs都是必要的,包括域间铰链弯曲和局部侧链重定向。Arg8和Glu64之间的盐桥稳定了闭合状态,并且在铰链弯曲时必须断开,而Phe4重新定向到疏水口袋以稳定开放状态。我们的结果强调了选择合适的cv和优化转向方案以防止蛋白质变形的重要性。这项工作表明,SMD模拟可以作为在缺乏高分辨率结构数据的情况下理解蛋白质构象变化的预测工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Minimal Collective Variables for Conformational Transitions in Steered and Temperature-Accelerated MD Simulations: A T4 Lysozyme Case Study.

Conformational transitions in proteins can be difficult to observe with equilibrium molecular dynamics and challenging for enhanced sampling methods like Targeted MD when high-resolution structural data are unavailable. Low-resolution data, such as interatomic distances and angles, can serve as collective variables (CVs) to bias steered MD (SMD) simulations, but the optimal choice and number of CVs remain unclear. Here, we identify a minimal set of CVs that drive successful transitions between metastable states in T4 lysozyme. We validate them using temperature-accelerated MD (TAMD) to accelerate conformational changes in the absence of target bias. We found that CVs at both the largest and smallest scales are necessary, including interdomain hinge bending and local side-chain reorientation. A salt bridge between Arg8 and Glu64 stabilizes the closed state and must break for hinge bending, while Phe4 reorients to a hydrophobic pocket to stabilize the open state. Our results highlight the importance of selecting appropriate CVs and optimizing the steering protocol to prevent protein deformation. This work demonstrates that SMD simulations can serve as a predictive tool for understanding protein conformational changes in the absence of high-resolution structural data.

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来源期刊
CiteScore
5.80
自引率
9.10%
发文量
965
审稿时长
1.6 months
期刊介绍: An essential criterion for acceptance of research articles in the journal is that they provide new physical insight. Please refer to the New Physical Insights virtual issue on what constitutes new physical insight. Manuscripts that are essentially reporting data or applications of data are, in general, not suitable for publication in JPC B.
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