Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0340, USA.
J Chem Inf Model. 2013 Aug 26;53(8):2047-56. doi: 10.1021/ci400225w. Epub 2013 Aug 9.
CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model of the lipid bilayer and the transmembrane helix are performed. The dynamics of aromatase and the role of titration of an important amino acid residue involved in aromatization of androgens are investigated via two 250-ns long simulations. One simulation treats the protonated form of the catalytic aspartate 309, which appears more consistent with crystallographic data for the active site, while the simulation of the deprotonated form shows some notable conformational shifts. Ensemble-based computational solvent mapping experiments indicate possible novel druggable binding sites that could be utilized by next-generation inhibitors. In addition, the effects of protonation on the ligand positioning and channel dynamics are investigated using geometrical models that estimate the opening width of critical channels. Significant differences in channel dynamics between the protonated and deprotonated trajectories are exhibited, suggesting that the mechanism for substrate and product entry and the aromatization process may be coupled to a "locking" mechanism and channel opening. Our results may be particularly relevant in the design of novel drugs, which may be useful therapeutic treatments of cancers such as those of the breast and prostate.
CYP19A1，也称为芳香酶或雌激素合成酶，是从相应雄激素生物合成雌激素的限速酶。几种临床上使用的乳腺癌治疗方法针对芳香酶。在这项工作中，对具有脂质双层和跨膜螺旋模型的芳香酶进行了明确溶剂化的全原子分子动力学模拟。通过两次 250-ns 长的模拟研究了芳香酶的动力学以及参与雄激素芳香化的重要氨基酸残基的滴定作用。一个模拟处理催化天冬氨酸 309 的质子化形式，这似乎与活性位点的晶体学数据更一致，而去质子化形式的模拟显示出一些明显的构象变化。基于集合的计算溶剂映射实验表明可能存在新的可药用结合位点，下一代抑制剂可以利用这些结合位点。此外，使用估计关键通道开口宽度的几何模型研究了质子化对配体定位和通道动力学的影响。质子化和去质子化轨迹之间表现出通道动力学的显着差异，表明底物和产物进入以及芳香化过程的机制可能与“锁定”机制和通道打开相关。我们的结果在设计新型药物时可能特别相关，这些药物可能对治疗乳腺癌和前列腺癌等癌症有用。
