Valdés-Tresanco Mario E, Valdés-Tresanco Mario S, Valiente Pedro A, Cocho Germinal, Mansilla Ricardo, Nieto-Villar J M
Computational Biology and Biomolecular Dynamics Laboratory, Center for Proteins Studies, Faculty of Biology, University of Havana, Havana, Cuba.
Faculty of Biology, University of Havana, Havana, Cuba.
J Mol Recognit. 2018 Jan;31(1). doi: 10.1002/jmr.2661. Epub 2017 Sep 12.
The calculation of absolute binding affinities for protein-inhibitor complexes remains as one of the main challenges in computational structure-based ligand design. The present work explored the calculations of surface fractal dimension (as a measure of surface roughness) and the relationship with experimental binding free energies of Plasmepsin II complexes. Plasmepsin II is an attractive target for novel therapeutic compounds to treat malaria. However, the structural flexibility of this enzyme is a drawback when searching for specific inhibitors. Concerning that, we performed separate explicitly solvated molecular dynamics simulations using the available high-resolution crystal structures of different Plasmepsin II complexes. Molecular dynamics simulations allowed a better approximation to systems dynamics and, therefore, a more reliable estimation of surface roughness. This constitutes a novel approximation in order to obtain more realistic values of fractal dimension, because previous works considered only x-ray structures. Binding site fractal dimension was calculated considering the ensemble of structures generated at different simulation times. A linear relationship between binding site fractal dimension and experimental binding free energies of the complexes was observed within 20 ns. Previous studies of the subject did not uncover this relationship. Regression model, coined FD model, was built to estimate binding free energies from binding site fractal dimension values. Leave-one-out cross-validation showed that our model reproduced accurately the absolute binding free energies for our training set (R = 0.76; <|error|> =0.55 kcal/mol; SD = 0.19 kcal/mol). The fact that such a simple model may be applied raises some questions that are addressed in the article.
蛋白质-抑制剂复合物绝对结合亲和力的计算仍然是基于计算结构的配体设计中的主要挑战之一。本研究探索了表面分形维数（作为表面粗糙度的一种度量）的计算以及与疟原虫蛋白酶II复合物实验结合自由能的关系。疟原虫蛋白酶II是新型抗疟治疗化合物的一个有吸引力的靶点。然而，在寻找特异性抑制剂时，这种酶的结构灵活性是一个缺点。针对这一点，我们使用不同疟原虫蛋白酶II复合物的可用高分辨率晶体结构进行了单独的显式溶剂化分子动力学模拟。分子动力学模拟能够更好地逼近系统动力学，从而更可靠地估计表面粗糙度。这是为了获得更现实的分形维数值而提出的一种新方法，因为之前的研究仅考虑了X射线结构。结合位点分形维数是根据在不同模拟时间生成的结构集合来计算的。在20纳秒内观察到结合位点分形维数与复合物的实验结合自由能之间存在线性关系。该主题的先前研究并未发现这种关系。构建了回归模型（称为FD模型），以根据结合位点分形维数值估计结合自由能。留一法交叉验证表明，我们的模型准确地重现了训练集的绝对结合自由能（R = 0.76；<|误差|> = 0.55千卡/摩尔；标准差 = 0.19千卡/摩尔）。这样一个简单模型能够应用这一事实引发了本文中讨论的一些问题。
