Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach.
Successful molecular dynamics simulation of the zinc-bound farnesyltransferase using the cationic dummy atom approach.
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发表时间：
2000-10
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通讯作者：
Y. Pang;Kun Xu;J. Yazal;F. Prendergast
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作者：
Y. Pang;Kun Xu;J. Yazal;F. Prendergast
法尼基转移酶（FT）抑制剂可以抑制肿瘤细胞增殖，而基本上不干扰正常细胞的生长，从而为癌症治疗带来希望。基于结构的方法来设计改进的FT抑制剂依赖于FT的含锌活性位点的构象灵活性的知识。虽然已经报道了FT的几种X射线结构，但关于酶的活性位点构象灵活性的详细信息仍然不可用。FT的分子动力学（MD）模拟可以提供必要的信息，但由于缺乏有效的方法来模拟蛋白质中锌的四配体配位而没有得到应用。在这里，我们详细报告的问题，发生在传统的MD模拟的锌绑定FT和解决这些问题，通过采用一种简单的方法，使用阳离子虚拟原子施加取向的锌配体的要求。一个成功的1.0 ns（1.0 fs时间步长）MD模拟锌结合FT表明，9个保守的残基（Asn127 α，Gln162 α，Asn165 α，Gln195 α，His248 β，Lys294 β，Leu295 β，Lys353 β，和Ser357 β）在哺乳动物FT的活性位点是相对移动的。这些残基中的一些可能参与配体诱导的活性位点构象重排结合后，值得关注的筛选和设计改进的FT抑制剂的癌症化疗。
Farnesyltransferase (FT) inhibitors can suppress tumor cell proliferation without substantially interfering with normal cell growth, thus holding promise for cancer treatment. A structure-based approach to the design of improved FT inhibitors relies on knowledge of the conformational flexibility of the zinc-containing active site of FT. Although several X-ray structures of FT have been reported, detailed information regarding the active site conformational flexibility of the enzyme is still not available. Molecular dynamics (MD) simulations of FT can offer the requisite information, but have not been applied due to a lack of effective methods for simulating the four-ligand coordination of zinc in proteins. Here, we report in detail the problems that occurred in the conventional MD simulations of the zinc-bound FT and a solution to these problems by employing a simple method that uses cationic dummy atoms to impose orientational requirement for zinc ligands. A successful 1.0 ns (1.0 fs time step) MD simulation of zinc-bound FT suggests that nine conserved residues (Asn127alpha, Gln162alpha, Asn165alpha, Gln195alpha, His248beta, Lys294beta, Leu295beta, Lys353beta, and Ser357beta) in the active site of mammalian FT are relatively mobile. Some of these residues might be involved in the ligand-induced active site conformational rearrangement upon binding and deserve attention in screening and design of improved FT inhibitors for cancer chemotherapy.