Folding simulations for proteins with diverse topologies are accessible in days with a physics-based force field and implicit solvent.
Folding simulations for proteins with diverse topologies are accessible in days with a physics-based force field and implicit solvent.
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DOI：
10.1021/ja5032776
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发表时间：
2014-10-08
影响因子：
15
通讯作者：
Simmerling, Carlos
中科院分区：
文献类型：
--
作者：
Hai Nguyen;Maier, James;Huang, He;Perrone, Victoria;Simmerling, Carlos
毫秒的时间尺度所需的分子动力学模拟接近蛋白质折叠的定量研究还不是常规的。延长模拟时间尺度的一种方法是在专门且昂贵的超级计算机（如Anton）上执行长时间模拟。然而，理想情况下，折叠模拟将更经济，同时保持合理的准确性，并提供反馈的结构，稳定性和功能足够快，如果直接与实验合作。解决这个问题的方法通常涉及准确性，精度和成本之间的各种妥协;这里的目标是解决简单的隐式溶剂模型是否已经变得足够准确，因为它们的弱点可以被它们快速提供更精确的构象数据的能力所抵消。我们证明，我们最近开发的基于物理学的模型在这一挑战中表现良好，能够准确地模拟17种蛋白质中16种蛋白质的全原子折叠，这些蛋白质具有各种大小，二级结构和拓扑结构。这些模拟是使用Amber软件在廉价的GPU上进行的，每个GPU每天提供2.1 μs，这里提供的数据>2.5 ms。我们还表明，17种蛋白质中有14种的天然构象优于错误折叠的结构。对于其他3个，错误折叠的结构是优先选择的，这表明有进一步改进的机会。
The millisecond time scale needed for molecular dynamics simulations to approach the quantitative study of protein folding is not yet routine. One approach to extend the simulation time scale is to perform long simulations on specialized and expensive supercomputers such as Anton. Ideally, however, folding simulations would be more economical while retaining reasonable accuracy, and provide feedback on structure, stability and function rapidly enough if partnered directly with experiment. Approaches to this problem typically involve varied compromises between accuracy, precision, and cost; the goal here is to address whether simple implicit solvent models have become sufficiently accurate for their weaknesses to be offset by their ability to rapidly provide much more precise conformational data as compared to explicit solvent. We demonstrate that our recently developed physics-based model performs well on this challenge, enabling accurate all-atom simulated folding for 16 of 17 proteins with a variety of sizes, secondary structure, and topologies. The simulations were carried out using the Amber software on inexpensive GPUs, providing ∼1 μs/day per GPU, and >2.5 ms data presented here. We also show that native conformations are preferred over misfolded structures for 14 of the 17 proteins. For the other 3, misfolded structures are thermodynamically preferred, suggesting opportunities for further improvement.
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影响因子：
5.5
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Simmerling, Carlos
影响因子：
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作者：
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通讯作者：
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