A computer model for the membrane binding of HIV-1 Gag

描述(申请人提供)：这项研究的总体目标是开发C型逆转录病毒在病毒组装过程中如何与受感染细胞质膜的胞浆表面相互作用的计算模型。人类免疫缺陷病毒1型(HIV-1)Gag多聚蛋白的膜结合需要N-末端基质(MA)序列中的肉豆蔻酸和碱性残基簇；其他逆转录病毒MA含有类似的基序。因此，第一个特定的目的是通过使用连续介质静电模型来计算它们与磷脂双层原子模型的物理相互作用，来验证这样的假设，即非特定的静电和疏水相互作用提供了足够的能量来解释已知结构的逆转录病毒MA的膜结合。尽管序列同源性很低，但MA具有相同的结构折叠。在每个MA结构中，一簇碱性残基位于分子的表面，尽管这些残基在线性序列空间中不保守。因此，在缺乏序列相似性的情况下，MA似乎具有结构和静电同源性。第二个具体目标是通过为未知结构的MA建立模型并计算它们的生物物理性质来测试这种观察的普遍性。为了促进对MA功能的新发现，例如静电相互作用在GAG靶向中发挥普遍作用的可能性，第三个具体目标是构建一个结合计算、实验和基因组信息的MA关系数据库。艾滋病毒需要一个流体膜包膜来保证其结构的完整性，因此不适用于传统的结构技术。这一建议为未来逆转录病毒组装和结构的全面计算机模型的计算工作奠定了基础。这项研究具有很高的创新性，因为通过关注其他方法不容易解决的问题，它将提供对病毒组装至关重要的蛋白质/膜相互作用的分子模型，可以用来提出扰乱子代病毒粒子产生的新的治疗方法。

DESCRIPTION (provided by applicant): The overall goal of this research is to develop computational models for how type C retroviruses interact with the cytosolic surface of the plasma membrane of infected cells during viral assembly. A myristate and cluster of basic residues in the N-terminal matrix (MA) sequence are required for membrane association of the Gag polyprotein from human immunodeficiency virus type 1 (HIV-1); other retroviral MAs contain similar motifs. Therefore, the first specific aim is to test the hypothesis that nonspecific electrostatic and hydrophobic interactions provide enough energy to account for the membrane binding of retroviral MAs of known structure by using continuum electrostatic models to calculate their physical interactions with atomic models of phospholipid bilayers. MAs share the same structural fold in spite of very low sequence identity. In each MA structure, a cluster of basic residues is located on the surface of the molecule even though these residues are not conserved in linear sequence space. Thus, MAs appear to share structural and electrostatic homology in the absence of sequence similarity. The second specific aim is to test the generality of this observation by building models for MAs of unknown structure and calculating their biophysical properties. In order to facilitate new discoveries about MA function, e.g. the possibility that electrostatic interactions play a general role in Gag targeting, the third specific aim is to construct a relational database which combines computational, experimental and genomic information on MAs. HIV requires a fluid membrane envelope for its structural integrity and is, thus, not amenable to traditional structural techniques. This proposal lays the foundation for future computational work on a comprehensive computer model of retroviral assembly and structure. The research is highly innovative because by focusing on questions that are not easily addressed by other methods, it will provide molecular models of the protein/membrane interactions crucial to viral assembly which can be used to suggest novel therapeutic approaches to disrupting the production of progeny virions.