Dipartimento di Chimica Fisica ed Elettrochimica, Università degli Studi di Milano, Via Golgi 19, Milano, Italy.
Nat Chem. 2009 Nov;1(8):642-8. doi: 10.1038/nchem.401. Epub 2009 Oct 23.
Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein-protein interface allows us to identify the amino acids responsible for tubulin-tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells.
微管是由微管蛋白二聚体自组装形成的聚合结构。这些动态结构的生长和收缩在细胞增殖过程中起着关键作用。这使得微管成为许多目前正在使用或正在临床试验中的抗癌药物的分子靶点。它们的显著成功受到治疗过程中耐药肿瘤细胞出现的限制，因此需要开发新的抗耐药分子。在这里，我们使用分子动力学和自由能计算来研究允许微管形成的相互作用网络。对蛋白质-蛋白质界面进行建模使我们能够识别负责微管蛋白-微管蛋白结合的氨基酸，从而设计与微管蛋白亚序列对应的肽，这些肽干扰微管的形成。我们表明，应用分子建模技术可鉴定出在体外和培养细胞中均具有抗微管蛋白活性的肽。
