EXPLORATION OF THE HUMAN ADENOVIRUS PROTEASE ACTIVATION PATHWAY VIA LONG TIMESC

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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一种酶，因此是抗病毒药物的靶点。该酶通过53个氨基酸的信号转导通路与小肽结合后被激活。我们使用了基于模拟退火法的微动弹性带(NEB)技术来预测AVP的低能垒激活途径。AVP失活形式和活性形式的共PI得到的晶体结构提供了激活途径的两个终点，NEB代码已被用于预测这一途径的中间体。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。一种是在pVIc多肽辅因子激活后立即从失活的酶结构开始，另一种是在去除激活的pVIc肽辅因子后立即从活性的酶结构开始。这些模拟将提供有关激活途径运动的关键信息，这些信息将为AVP抑制提供特定的靶点位置，并为更深入的NEB研究提供种子结构。

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.