Department of Physics, University of Cyprus, P.O 20537, CY678 Nicosia, Cyprus.
Laboratoire de Biochimie (CNRS UMR7654), Ecole Polytechnique, Palaiseau, France.
J Chem Phys. 2020 Aug 7;153(5):054113. doi: 10.1063/5.0013320.
Computational protein design relies on simulations of a protein structure, where selected amino acids can mutate randomly, and mutations are selected to enhance a target property, such as stability. Often, the protein backbone is held fixed and its degrees of freedom are modeled implicitly to reduce the complexity of the conformational space. We present a hybrid method where short molecular dynamics (MD) segments are used to explore conformations and alternate with Monte Carlo (MC) moves that apply mutations to side chains. The backbone is fully flexible during MD. As a test, we computed side chain acid/base constants or pK's in five proteins. This problem can be considered a special case of protein design, with protonation/deprotonation playing the role of mutations. The solvent was modeled as a dielectric continuum. Due to cost, in each protein we allowed just one side chain position to change its protonation state and the other position to change its type or mutate. The pK's were computed with a standard method that scans a range of pH values and with a new method that uses adaptive landscape flattening (ALF) to sample all protonation states in a single simulation. The hybrid method gave notably better accuracy than standard, fixed-backbone MC. ALF decreased the computational cost a factor of 13.
计算蛋白质设计依赖于蛋白质结构的模拟，在这种模拟中，选定的氨基酸可以随机突变，然后选择突变来增强目标性质，如稳定性。通常，蛋白质骨架保持固定，其自由度通过隐式建模来降低构象空间的复杂性。我们提出了一种混合方法，其中使用短的分子动力学 (MD) 片段来探索构象，并与蒙特卡罗 (MC) 移动交替进行，后者将突变应用于侧链。在 MD 过程中，骨架完全灵活。作为一个测试，我们计算了五个蛋白质中的侧链酸碱常数或 pK 值。这个问题可以被认为是蛋白质设计的一个特例，其中质子化/去质子化起着突变的作用。溶剂被建模为介电连续体。由于成本限制，在每种蛋白质中，我们只允许一个侧链位置改变其质子化状态，而另一个位置改变其类型或突变。pK 值是使用标准方法计算的，该方法扫描一系列 pH 值，以及使用新的自适应景观扁平化 (ALF) 方法在单个模拟中采样所有质子化状态。与标准的固定骨架 MC 相比，混合方法显著提高了准确性。ALF 将计算成本降低了 13 倍。
