EXPLORATION OF THE HUMAN ADENOVIRUS PROTEASE ACTIVATION PATHWAY VIA LONG TIMESC

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 腺病毒蛋白酶（AVP）是病毒复制所必需的酶，因此是抗病毒药物的靶标。该酶通过53个氨基酸的信号转导途径与小肽结合后被激活。我们已经使用模拟退火基于轻推弹性带（NEB）技术内实现的版本11的AMBER分子动力学代码来预测低能量势垒激活AVP的途径。晶体结构获得的co-PI的AVP和活性形式提供了两个端点的激活途径和NEB代码已被用来预测中间体沿着这条途径。然而，NEB方法必然会对实际路径施加限制。AVP无偏激活途径的模拟将为下一代抗病毒药物的开发提供关键信息。我们计划运行两个25 s无偏MD轨迹。第一种在用pVIc肽辅因子活化后立即从无活性酶结构开始，另一种在除去活化性pVIc肽辅因子后立即从活性酶结构开始。这些模拟将提供关于运动的关键信息沿着激活途径，这将提供特定的目标位置AVP抑制，也提供种子结构更深入的NEB研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The adenovirus protease (AVP) is an enzyme essential for virus replication and hence is a target for antiviral drugs. The enzyme is activated upon the binding of a small peptide via a 53 amino acid signal transduction pathway. We have used simulated annealing based Nudged Elastic Band (NEB) techniques implemented within version 11 of the AMBER molecular dynamics code to predict low energy barrier activation pathways of AVP. Crystal structures obtained by the co-PI of both the inactivate and active forms of AVP provide the two end points of the activation pathway and the NEB code has been used to predict intermediates along this pathway. However, the NEB method necessarily places restrictions on the actual pathway. The simulation of unbiased activation pathways for AVP will provide critical information in the development of next generation antiviral drugs. We plan to run two 25 ¿s unbiased MD trajectories. The first starting from the inactive enzyme structure immediately after activation with the pVIc peptide cofactor and the other starting from the active enzyme structure immediately after the removal of the activating pVIc peptide cofactor. These simulations will provide critical information regarding motions along the activation pathway that will provide specific target locations for AVP inhibition and also provide seed structures for more in-depth NEB investigations.