Insights from molecular dynamics simulations for computational protein design.
Insights from molecular dynamics simulations for computational protein design.
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DOI：
10.1039/c6me00083e
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发表时间：
2017-02-01
影响因子：
3.6
通讯作者：
Daggett V
中科院分区：
文献类型：
--
作者：
Childers MC;Daggett V
结构生物学领域的一个巨大挑战是设计和工程蛋白具有针对性功能。尽管在这方面取得了很大的成功，但设计成功率仍然很低，这是我们对氨基酸序列和所采用结构之间关系的有限理解的不断提醒。除了实验技术和合理的设计策略外，还采用了计算方法来帮助蛋白质的设计和工程。分子动力学（MD）就是一种根据经典动力学模拟蛋白质运动的方法。在这里，我们回顾了对从MD模拟得出的蛋白质动力学的见解如何影响蛋白质的设计。医学博士最大的优势之一是它的能力是揭示超出蛋白质数据库中静态结构中可用内容的信息。在这方面，模拟可以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来直接引导蛋白质设计。 MD模拟也可以用作虚拟筛选工具，以排名，选择，识别和评估潜在的设计。 MD唯一地准备为蛋白质设计工作提供信息，在该应用中，应用需要对蛋白质动力学和原子水平描述动力学与功能之间的关系的描述。在这里，我们通过提供有关控制稳定性和功能的构象，构象过渡，相互作用和动力学的信息来调查MD模拟来调节蛋白质稳定性和蛋白质功能的情况。此外，我们讨论了蛋白质折叠/展开模拟的构象已被利用用于蛋白质设计的情况，从而产生了无法从静态结构获得的新型结果。
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.