Exhaustively Sampling Peptide Adsorption with Metadynamics
Exhaustively Sampling Peptide Adsorption with Metadynamics
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DOI：
10.1021/la4010664
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发表时间：
2013-06-25
期刊：
影响因子：
3.9
通讯作者：
Pfaendtner, Jim
中科院分区：
文献类型：
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作者：
Deighan, Michael;Pfaendtner, Jim
由于许多原因，模拟肽或蛋白质的吸附并获得热力学可观测量的定量估计仍然具有挑战性。一个原因是缺乏分子尺度的实验数据来验证这种计算模型。我们也缺乏模拟方法，有效地解决模拟蛋白质吸附的双重挑战：克服强表面结合和采样构象变化。无偏的经典模拟没有解决这些挑战。以前应用增强采样的尝试通常只关注这两个问题中的一个，而将另一个留给机会或蛮力计算。为了提高我们的能力，准确地解决吸附的蛋白质的方向和构象状态，我们已经应用了平行回火Metadaptics在良好的回火Enchantment（PTMetaD-WTE）的方法，几个明确的溶剂化蛋白质/表面系统。我们模拟了两个肽，LK α 14和LK β 15，到两个自组装单层（SAM）表面的羧基和甲基末端功能的吸附行为。PTMetaD-WTE被证明是有效的，在实现快速收敛的模拟，其结果阐明了肽吸附的不同方面，包括：结合自由能，侧链的方向，和首选的构象。我们研究了表面/蛋白质界面的特定分子特征如何改变多维肽结合自由能景观的形状。此外，我们比较了我们的增强采样技术与伞形采样，并评估了三种常用的分子动力学力场。
Simulating the adsorption of a peptide or protein and obtaining quantitative estimates of thermodynamic observables remains challenging for many reasons. One reason is the dearth of molecular scale experimental data available for validating such computational models. We also lack simulation methodologies that effectively address the dual challenges of simulating protein adsorption: overcoming strong surface binding and sampling conformational changes. Unbiased classical simulations do not address either of these challenges. Previous attempts that apply enhanced sampling generally focus on only one of the two issues, leaving the other to chance or brute force computing. To improve our ability to accurately resolve adsorbed protein orientation and conformational states, we have applied the Parallel Tempering Metadynamics in the Well-Tempered Ensemble (PTMetaD-WTE) method to several explicitly solvated protein/surface systems. We simulated the adsorption behavior of two peptides, LK alpha 14 and LK beta 15, onto two self-assembled monolayer (SAM) surfaces with carboxyl and methyl terminal functionalities. PTMetaD-WTE proved effective at achieving rapid convergence of the simulations, whose results elucidated different aspects of peptide adsorption including: binding free energies, side chain orientations, and preferred conformations. We investigated how specific molecular features of the surface/protein interface change the shape of the multidimensional peptide binding free energy landscape. Additionally, we compared our enhanced sampling technique with umbrella sampling and also evaluated three commonly used molecular dynamics force fields.