Force field development for zinc metalloproteins

描述(由申请人提供)：本提案旨在开发新的可转移的非键合力场来模拟锌金属蛋白和设计锌酶抑制剂。锌蛋白在许多生物过程中扮演着重要的角色，人们越来越认识到它们在生物学和医学上的重要性。例如，锌依赖的组蛋白脱乙酰酶(HDAC)在转录抑制和基因沉默中起着关键作用，是开发抗癌和其他各种疾病新疗法的最具吸引力的靶点之一。因此，迫切需要强大的计算方法来帮助表征锌金属蛋白的结构和动力学，并促进锌酶抑制剂的设计和排序。然而，这一方向的进展一直受到很大的阻碍，主要是因为缺乏可转移的成对力场来充分描述锌的配位。目前的主流观点认为，这样的力场可能是不可能的，有必要超越成对的非成键模型，以合理地描述锌的配位。在我们的初步研究中，我们发现了一种新的实用策略来克服这一固有的挑战，即设计短-长有效函数(SLEF)来处理锌离子与所有其他原子之间的静电相互作用。我们的初步结果表明，这种SLEF方法非常有希望充分模拟灵活的锌配位。在这里，我们建议开发SLEF力场来模拟锌金属蛋白，并开发SLEF评分函数来将配体对接到锌酶中。为琥珀和Autodock软件开发的SLEF补丁以及教程和测试集将免费提供给公众。

DESCRIPTION (provided by applicant): This proposal is directed at developing novel transferable non-bonded force fields to model zinc metalloproteins and to design zinc enzyme inhibitors. Zinc proteins play essential roles in many biological processes, and there is an increasing appreciation of their biological and medical importance. For example, zinc-dependent histone deacetylases (HDACs) play a critical role in transcriptional repression and gene silencing, and are among the most attractive targets for the development of new therapeutics against cancer and various other diseases. Thus, robust computational approaches are greatly needed to help characterize the structure and dynamics of zinc metalloproteins, and to facilitate the design and ranking of zinc enzyme inhibitors. However, progress along this direction has been very much impeded mainly due to the lack of transferable pairwise force fields to adequately describe zinc coordination. The current dominant view is that such a force field may not be possible and that it would be necessary to go beyond the pairwise non-bonded model for reasonable description of the zinc coordination. In our preliminary studies, we have discovered a novel practical strategy to overcome this inherent challenge, which is to design short-long effective functions (SLEF) to treat electrostatic interactions between the zinc ion and all other atoms. Our preliminary results indicated that this SLEF approach is very promising to adequately model flexible zinc coordination. Here we propose to develop SLEF force fields to simulate zinc metalloproteins, and to develop SLEF scoring functions for docking ligands into zinc enzymes. The developed SLEF patches to the AMBER and Autodock softwares as well as tutorials and test sets will be made freely available to the public.