Accurate Structure Prediction for Protein Loops Based on Molecular Dynamics Simulations with RSFF2C
Accurate Structure Prediction for Protein Loops Based on Molecular Dynamics Simulations with RSFF2C
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DOI：
10.1021/acs.jctc.1c00341
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发表时间：
2021-06-25
影响因子：
5.5
通讯作者：
Wu, Yun-Dong
中科院分区：
文献类型：
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作者：
Feng, Jia-Jie;Chen, Jia-Nan;Wu, Yun-Dong
连接α螺旋和β链的蛋白质环参与许多重要的生物过程。然而，由于其构象灵活性，通过实验和计算准确确定长环的三维（3D）结构仍然具有挑战性。在此，我们通过总计约 850 μs 的分子动力学 (MD) 模拟对蛋白质环结构预测进行了系统研究。对于一组 15 个长（10-16 个残基）和溶剂暴露的环，我们首先评估了四种最先进的环建模算法（DaReUS-Loop、Sphinx、Rosetta-NGK 和 MODELLER）在每个环上的性能，但它们都无法准确预测大多数环的结构。然后，使用三个最近的力场进行温度复制交换分子动力学 (REMD) 模拟：RSFF2C 与 TIP3P 水模型、CHARMM36m 与 CHARMM 修改的 TIP3P 以及 AMBER ff19SB 与 OPC。我们发现，我们最近开发的残留物特异性力场 RSFF2C 表现最好，并成功预测了 15 个循环中的 12 个，均方根偏差 (RMSD) < 1.5 埃。作为计算成本较低的替代方案，研究了高温（380、500 和 620 K）下的正常 MD 模拟。观察了每个力场的温度相关性能，并且对于 RSFF2C+TIP3P，我们发现 500 K 下的三个独立 100 ns MD 模拟给出了与 REMD 模拟相当的结果。这些结果表明，MD 模拟，特别是使用增强的采样技术（例如副本交换）和 RSFF2C 力场，可用于准确的环路结构预测。
Protein loops, connecting the alpha-helices and beta-strands, are involved in many important biological processes. However, due to their conformational flexibility, it is still challenging to accurately determine three-dimensional (3D) structures of long loops experimentally and computationally. Herein, we present a systematic study of the protein loop structure prediction via a total of similar to 850 mu s molecular dynamics (MD) simulations. For a set of 15 long (10-16 residues) and solvent-exposed loops, we first evaluated the performance of four state-of-the-art loop modeling algorithms, DaReUS-Loop, Sphinx, Rosetta-NGK, and MODELLER, on each loop, and none of them could accurately predict the structures for most loops. Then, temperature replica exchange molecular dynamics (REMD) simulations were conducted with three recent force fields, RSFF2C with TIP3P water model, CHARMM36m with CHARMM-modified TIP3P, and AMBER ff19SB with OPC. We found that our recently developed residue-specific force field RSFF2C performed the best and successfully predicted 12 out of 15 loops with a root-mean-square deviation (RMSD) < 1.5 angstrom. As an alternative with lower computational cost, normal MD simulations at high temperatures (380, 500, and 620 K) were investigated. Temperature-dependent performance was observed for each force field, and, for RSFF2C+TIP3P, we found that three independent 100-ns MD simulations at 500 K gave comparable results with REMD simulations. These results suggest that MD simulations, especially with enhanced sampling techniques such as replica exchange, with the RSFF2C force field could be useful for accurate loop structure prediction.