A grand challenge in the field of structural biology is to design and engineer proteins that exhibit targeted functions. Although much success on this front has been achieved, design success rates remain low, an ever-present reminder of our limited understanding of the relationship between amino acid sequences and the structures they adopt. In addition to experimental techniques and rational design strategies, computational methods have been employed to aid in the design and engineering of proteins. Molecular dynamics (MD) is one such method that simulates the motions of proteins according to classical dynamics. Here, we review how insights into protein dynamics derived from MD simulations have influenced the design of proteins. One of the greatest strengths of MD is its capacity to reveal information beyond what is available in the static structures deposited in the Protein Data Bank. In this regard simulations can be used to directly guide protein design by providing atomistic details of the dynamic molecular interactions contributing to protein stability and function. MD simulations can also be used as a virtual screening tool to rank, select, identify, and assess potential designs. MD is uniquely poised to inform protein design efforts where the application requires realistic models of protein dynamics and atomic level descriptions of the relationship between dynamics and function. Here, we review cases where MD simulations was used to modulate protein stability and protein function by providing information regarding the conformation(s), conformational transitions, interactions, and dynamics that govern stability and function. In addition, we discuss cases where conformations from protein folding/unfolding simulations have been exploited for protein design, yielding novel outcomes that could not be obtained from static structures.

中文翻译：

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分子动力学模拟对计算蛋白质设计的见解。

结构生物学领域的一大挑战是设计和改造具有目标功能的蛋白质。尽管在这方面已经取得了很多成功，但设计成功率仍然很低，这永远提醒我们对氨基酸序列与它们采用的结构之间的关系的了解有限。除了实验技术和合理的设计策略，还采用了计算方法来辅助蛋白质的设计和工程。分子动力学（MD）是一种根据经典动力学模拟蛋白质运动的方法。在这里，我们回顾了从MD模拟得出的对蛋白质动力学的见识如何影响蛋白质的设计。MD的最大优势之一是它能够显示超出蛋白质数据库中静态结构中可用信息的信息。在这方面，通过提供有助于蛋白质稳定性和功能的动态分子相互作用的原子细节，模拟可用于直接指导蛋白质设计。MD仿真也可以用作虚拟筛选工具，以对潜在设计进行排名，选择，识别和评估。MD的独特之处在于可以为蛋白质设计工作提供信息，其中该应用程序需要蛋白质动力学的逼真的模型以及动力学与功能之间关系的原子级描述。在这里，我们回顾了使用MD模拟通过提供有关构象，构象转变，相互作用以及控制稳定性和功能的动力学。此外，我们讨论了蛋白质折叠/展开模拟中的构象已被用于蛋白质设计的情况，产生了无法从静态结构获得的新颖结果。