Biomolecular simulation to elucidate small-molecule modulation of mechanosensor protein.
Biomolecular simulation to elucidate small-molecule modulation of mechanosensor protein.
复制标题
生物分子模拟阐明机械传感器蛋白的小分子调节。
DOI：
10.1073/pnas.2319968121
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发表时间：
2024
影响因子：
11.1
通讯作者：
Li,Jianing
中科院分区：
文献类型：
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作者：
Li,Jianing
生物分子模拟的潜力已经达到了前所未有的高度（1，2），这要归功于力场参数，蛋白质结构表征和预测以及高性能计算的重大进展。Allatom模拟的新记录每天都在实现，不仅增加了可访问的长度和时间尺度，而且增加了所讨论系统的复杂性。现在可以很容易地建立和模拟更多的生物学相关模型，提供一个“计算显微镜”（3）来理解基本过程（4），如蛋白质折叠/解折叠，配体结合/解结合，复合物形成/解离等。生物分子模拟提供了对蛋白质和DNA作用的机械见解。RNA分子在其天然环境中以及这些系统如何在不同条件下进化（例如，突变，正构或变构调节，温度，pH值，盐度等）（五）、这种由模拟提供的丰富的生物学信息反过来可以帮助识别潜在的治疗靶点并设计新的疾病治疗药物。生物分子动力学（MD）模拟在20年前被认为是一种昂贵或低效的技术，现在已经成为现代药物发现的主要工具。随着几十年来硬件和软件技术的发展，生物分子MD模拟不再代表单一的方法。虽然无偏MD模拟允许研究人员观察分子的移动和相互作用，但许多增强的采样和自由能模拟方法现在可以为我们的问题提供更多的定量答案（4），例如估计结合自由能。因此，正交MD模拟方法的组合使用对于研究生物分子复合物的动力学和热力学是强大的，这一壮举可能是具有挑战性的，以实现与其他现代技术的类似系统。在这一期的PNAS中，你可以找到一个很好的例子，说明如何采用正交模拟方法来研究小分子
The potency of biomolecular simulation has reached unprecedented heights (1, 2), thanks to major advances in force field parameters, protein structure characterization and prediction, and high-performance computing. New records of allatom simulations are being achieved every day, increasing not only the length and time scales accessible but also the complexity of the system in question. More biologically relevant models can now readily be built and simulated, providing a “computational microscope”(3) to understand basic processes (4) like protein folding/unfolding, ligand binding/unbinding, complex formation/dissociation, etc. Building on the knowledge of these processes, biomolecular simulation offers mechanistic insight into the role of proteins and DNA/RNA molecules within their native environments and how these systems evolve with varying conditions (eg, mutation, orthosteric or allosteric modulation, temperature, pH, salinity, etc.)(5). This rich biological information provided by simulations can, in turn, help to identify potential therapeutic targets and design novel therapeutic agents for diseases. Seen as an expensive or inefficient technique 20 y ago, biomolecular molecular dynamics (MD) simulation has become a major tool for modern drug discovery. With technique evolving alongside hardware and software over the decades, biomolecular MD simulation is no longer representative of a single approach. While unbiased MD simulations allow researchers to watch molecules moving and interacting, many enhanced sampling and free energy simulation approaches can now provide more quantitative answers to our questions (4), such as estimating the binding free energies. Therefore, the combined use of orthogonal MD simulation approaches is powerful for studying the kinetics and thermodynamics of biomolecular complexes, a feat that can be challenging to achieve with other modern techniques for analogous systems. In this issue of PNAS, you can find an excellent example of how orthogonal simulation approaches are employed to study the small-molecular