1)德州学院健康医学院,新型药用辅料与缓控释制剂山东省工程研究中心,德州 253023;2)德州学院生物物理研究院,德州 253023
国家自然科学基金(32571444)和山东省自然科学基金(ZR2025MS280,ZR2024QC369)资助项目。
1)Shandong Provincial Engineering Research Center of Novel Pharmaceutical Excipients Sustained and Controlled Release Preparations, School of Health and Medicine, Dezhou University, Dezhou 253023, China;2)Institute of Biophysics, Dezhou University, Dezhou 253023, China
This work was supported by grants from The National Natural Science Foundation of China (32571444) and the Natural Science Foundation of Shandong Province (ZR2025MS280, ZR2024QC369).
蛋白质等生物大分子的功能实现依赖于构象动态变化及变构调控,对其分子机制的解析是理解生命过程的重要基础。分子动力学模拟是探究其原子水平构象演化的有力工具,但传统方法受模拟时间尺度与高自由能势垒限制,难以有效捕捉稀有构象及其转变路径,增强采样技术的发展成为突破这一瓶颈的关键。元动力学作为经典增强采样技术,存在对集体变量高度依赖以及偏置势累积误差显著等缺陷。本文评述3类核心改进策略:随机重置与元动力学相结合方法,通过轨迹重置机制提升采样效率且规避集体变量优化难题;SinkMeta方法利用“下沉”偏置效应实现特定区域及路径的高效探索;OPES混合方法则通过优化目标分布或偏置构建方式,提高自由能估计的稳定性。这些方法为复杂生物体系自由能景观刻画和构象转变研究提供了新思路,并推动了增强采样方法的持续发展。
The functional realization of proteins and other biological macromolecules depends on conformational dynamics and allosteric regulation, and elucidating their molecular mechanisms is an important foundation for understanding life processes. Molecular dynamics simulations are a powerful tool for investigating conformational evolution at the atomic level. However, traditional methods are limited by simulation timescales and high free-energy barriers, making it difficult to effectively capture rare conformations and their transition pathways. As a result, the development of enhanced sampling techniques has become key to overcoming this bottleneck. As a classical enhanced sampling technique, metadynamics suffers from several shortcomings, including strong dependence on collective variables and significant errors caused by bias potential accumulation. This article reviews three major improvement strategies. The first combines stochastic resetting with metadynamics, using trajectory-resetting mechanisms to improve sampling efficiency while avoiding the difficulty of optimizing collective variables. The second, SinkMeta, employs a “sinking” bias effect to enable efficient exploration of specific regions and paths. The third, OPES-based hybrid methods, improve the stability of free-energy estimation by optimizing the target distribution or the way the bias is constructed. These methods provide new ideas for characterizing free-energy landscapes and studying conformational transitions in complex biological systems, while also promoting the continued development of enhanced sampling methodologies.
童明琼,尹跃文,史志宏,曹赞霞.元动力学增强采样方法的改进及最新进展[J].生物化学与生物物理进展,2026,53(6):1793-1797 TONG Ming-Qiong, YIN Yue-Wen, SHI Zhi-Hong, CAO Zan-Xia. Improvements and Recent Advances of Metadynamics Enhanced Sampling Method[J]. Progress in Biochemistry and Biophysics,2026,53(6):1793-1797
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